Phenylalanine derivatives as alpha 4 integrin inhibitors

ABSTRACT

Disclosed are a series of phenylalanine derivatives, to compositions containing them, to processes for their preparation, and to their use in medicine.

[0001] This invention relates to a series of phenylalanine derivatives,to compositions containing them, to processes for their preparation, andto their use in medicine.

[0002] Over the last few years it has become increasingly clear that thephysical interaction of inflammatory leukocytes with each other andother cells of the body plays an important role in regulating immune andinflammatory responses [Springer, T A. Nature, 346 425, (1990);Springer, T. A. Cell 76, 301, (1994)]. Many of these interactions aremediated by specific cell surface molecules collectively referred to ascell adhesion molecules.

[0003] The adhesion molecules have been sub-divided into differentgroups on the basis of their structure. One family of adhesion moleculeswhich is believed to play a particularly important role in regulatingimmune and inflammatory responses is the integrin family. This family ofcell surface glycoproteins has a typical non-covalently linkedheterodimer structure. At least 14 different integrin α chains and 8different integrin P chains have been identified [Sonnenberg, A CurrentTopics in Microbiology and Immunology, 18, 7, (1993)]. The members ofthe family are typically named according to their heterodimercomposition although trivial nomenclature is widespread in this field.Thus the integrin termed α4β7 consists of the integrin α4 chainassociated with the integrin β1 chain, but is also widely referred to asVery Late Antigen 4 or VLA4. Not all of the potential pairings ofintegrin α and β chains have yet been observed in nature and theintegrin family has been subdivided into a number of subgroups based onthe pairings that have been recognized [Sonnenberg, A., ibid.].

[0004] The importance of cell adhesion molecules in human leukocytefunction has been further highlighted by a genetic deficiency diseasecalled Leukocyte Adhesion Deficiency (LAD) in which one of the familiesof leukocyte integrins is not expressed [Marlin, S. D. et al., Exp. Med.164, 855 (1986)]. Patients with this disease have a reduced ability torecruit leukocytes to inflammatory sites and suffer recurrent infectionswhich in extreme cases may be fatal.

[0005] The potential to modify adhesion molecule function in such a wayas to beneficially modulate immune and inflammatory responses has beenextensively investigated in animal models using specific monoclonalantibodies that block various functions of these molecules [e.g.Issekutz, T. B. J. Immunol. 3394, (1992); Li, Z. et al., Am. J. Physiol.263, L723, (1992); Binns, R. M. et al., J. Immunol. 157,, 4094, (1996)].A number of monoclonal antibodies which block adhesion molecule functionare currently being investigated for their therapeutic potential inhuman disease.

[0006] One particular integrin subgroup of interest involves the α4chain which can pair with two different β chains β1 and β7 [Sonnenberg,A. ibid]. The α4β1 pairing occurs on many circulating leukocytes (forexample, lymphocytes, monocytes and eosinophils) although it is absentor only present at low levels on circulating neutrophils. α4β1 binds toan adhesion molecule (Vascular Cell Adhesion Molecule-1 also known asVCAM-1) frequently up-regulated on endothelial cells at sites ofinflammation [Osborne, L. Cell, 62, 3, (1990)]. The molecule has alsobeen shown to bind to at least three sites in the matrix moleculefibronectin [Humphries, M. J., et al., Ciba Foundation Symposium, 189,177, (1995)]. Based on data obtained with monoclonal antibodies inanimal models it is believed that the interaction between α4β1 andligands on other cells and the extracellular matrix plays an importantrole in leukocyte migration and activation [Yednock, T. A, et al.,Nature, 356, 63, (1992); Podolsky, D. K., et al., J. Clin. Invest. 92,373, (1993); Abraham, W. M., et al., J. Clin. Invest. 93, 776, (1994)].

[0007] The integrin generated by the pairing of α4 and β7 has beentermed LPAM-1 [Holzmann, B and Weissman, I. EMBO J. 8, 1735, (1989)] andlike α4β1, binds to VCAM-1 and fibronectin. In addition, α4β7 binds toan adhesion molecule believed to be involved in the homing of leukocytesto mucosal tissue termed MAdCAM-1 [Berlin, C. et al., Cell, 74, 185,(1993)]. The interaction between α4β7 and MAdCAM-1 may also be importantat sites of inflammation outside of mucosal tissue [Yang, X-D. et al.,PNAS, 91, 12604 (1994)].

[0008] Regions of the peptide sequence recognized by α4β1 and α4β7 whenthey bind to their ligands have been identified. α4β1 seems to recognizeLDV, IDA or REDV peptide sequences in fibronectin and a QIDSP sequencein VCAM-1 [Humphries, M. J. et al., ibid] while α4β7 recognizes a LDTsequence in MAdCAM-1 [Briskin, M. J. et al., J. Immunol. 156, 719,(1996)]. There have been several reports of inhibitors of theseinteractions being designed from modifications of these short peptidesequences [Cardarelli, P. M. et al., J. Biol. Chem. 269, 18668, (1994):Sbroff. H. N. Bioorganic. Med. Chem. Lett. 6, 2495, (1996); Vanderslice,P. J. Immunol. 158, 1710, (1997)]. It has also been reported that ashort peptide sequence derived from the α4β1 binding site in fibronectincan inhibit a contact hypersensitivity reaction in atrinitrochlorobenzene sensitized mouse [Ferguson, T. A. et al., PNAS 88,8072, (1991)].

[0009] Since the alpha 4 subgroup of integrins are predominantlyexpressed on leukocytes their inhibition can be expected to bebeneficial in a number of immune or inflammatory disease states.However, because of the ubiquitous distribution and wide range offunctions performed by other members of the integrin family it is veryimportant to be able to identify selective inhibitors of the alpha 4subgroup.

SUMMARY OF THE INVENTION

[0010] This invention is directed to a group of compounds which arepotent and selective inhibitors of α4 integrins. Members of the groupare able to inhibit α4 integrins such as α4β1 and/or α4β7 atconcentrations at which they generally have no or minimal inhibitoryaction on a integrins of other subgroups. The compounds are thus of usein medicine, for example in the prophylaxis and treatment of immune orinflammatory disorders as described hereinafter.

[0011] Thus according to one aspect of the invention we provide acompound of formula (I):

[0012] wherein

[0013] R¹ and R² are independently selected from the group consisting ofhydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,cycloalkyl, substituted cycloalkyl, or R¹ and R², together with thenitrogen atom to which they are attached, are joined to form anoptionally substituted heterocyclic ring provided that said substitutedalkyl, substituted alkenyl and substituted cycloalkyl do not carry anaryl, substituted aryl, heteroaryl or substituted heteroaryl group;

[0014] R⁴ and R⁵ are independently selected from the group consisting of-L²(Alk³)_(t)L³(R⁷)_(u) in which L² and L³ are independently a covalentbond or a linker atom or group, t is zero or the integer 1, u is aninteger 1, 2, or 3, Alk³ is an aliphatic or heteroaliphatic chain and R⁷is hydrogen or halogen atom or a group selected from alkyl, —OR⁸ [whereR⁸ is a hydrogen atom or an optionally substituted alkyl group], —SR⁸,—NR⁸R⁹ [where R⁸ is a hydrogen atom or an optionally substituted alkylgroup], —NO₂, —CN, —CO₂R⁸, —SO₃H, —SOR⁸, —SO₂R⁸, —OCO₂R⁸, —CONR⁸R⁹,—CSNR⁸R⁹, —COR⁸, —OCOR⁸, —N(R⁸)COR⁹, —N(R⁸)CSR⁹, —SO₂N(R⁸)(R⁹),—N(R⁸)SO₂R⁹, —N(R⁸)CON(R⁹)(R¹⁰), [where R¹⁰ is a hydrogen atom or anoptionally substituted alkyl group], —N(R⁸)CSN(R⁹)(R¹⁰) or—N(R⁸)SO₂N(R⁹)(R¹⁰);

[0015] Alk² is a straight or branched alkylene chain;

[0016] m is zero or an integer 1;

[0017] R⁶ is a hydrogen atom or a methyl group;

[0018] R is a carboxylic acid (—CO₂H) or a derivative thereof;

[0019] R^(a) is a hydrogen or a methyl group;

[0020] Ar is an optionally substituted aromatic or heteroaromatic group;

[0021] and the salts, solvates, hydrates and N-oxides thereof.

[0022] One preferred group of compounds of this invention includecompounds of formula (2):

[0023] wherein R, R^(a), R¹, R², R⁶, Alk², m and Ar are as defined aboveand the salts, solvates, hydrates and N-oxides thereof.

[0024] Another class of compounds of this invention is where Ar isselected from the group consisting of moieties of formula IIIa, IIIc,IIId, IIIe or IIIf:

[0025] wherein

[0026] R^(5′) is selected from the group consisting of alkyl,substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl,cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, heterocyclic, substituted heterocylic, heteroaryl andsubstituted heteroaryl;

[0027] R^(6′) is selected from the group consisting of hydrogen, alkyl,substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl,substituted cycloalkenyl, heterocyclic, substituted heterocyclic, aryl,substituted aryl, heteroaryl, substituted heteroaryl, and —SO₂R^(10′)where R^(10′) is selected from the group consisting of alkyl,substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl,substituted cycloalkenyl, heterocyclic, substituted heterocyclic, aryl,substituted aryl, heteroaryl, substituted heteroaryl;

[0028] R^(7′) and R^(8′) are independently selected from the groupconsisting of hydrogen, alkyl, substituted alkyl, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic, substituted heterocyclic and halogen;

[0029] R^(16′) and R^(17′) are independently selected from the groupconsisting of hydrogen, alkyl, substituted alkyl, alkoxy, substitutedalkoxy, amino, substituted amino, cycloalkyl, substituted cycloalkyl,aryl, substituted aryl, heteroaryl, substituted heteroaryl,heterocyclic, substituted heterocyclic and halogen; and

[0030] R^(18′) is selected from the group consisting of alkyl,substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino,cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, heterocyclic and substituted heterocyclic;

[0031] R^(20′) is selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl, substitutedcycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,heterocyclic, substituted heterocyclic and halogen;

[0032] R^(21′) is selected from the group consisting of alkyl,substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino,cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocyclicand substituted heterocyclic;

[0033] b is 1 or 2;

[0034] and enantiomers, diastereomers and pharmaceutically acceptablesalts thereof.

[0035] It will be appreciated that compounds of formula (I) and (II) mayhave one or more chiral centres, and exist as enantiomers ordiastereomers. The invention is to be understood to extend to all suchenantiomers, diastereomers and mixtures thereof, including racemates.Formulae (I) and (II) and the formulae hereinafter are intended torepresent all individual isomers and mixtures thereof, unless stated orshown otherwise.

[0036] In the compounds of formulae (1) and (2), derivatives of thecarboxylic acid group, R, include carboxylic acid esters and amides.Particular esters and amides include —CO₂Alk⁵ and —CONR⁸R⁹ groups asdescribed herein.

[0037] Alk² in the compounds of the invention may be for example astraight or branched C₁₋₃ alkylene chain. Particular examples include—CH₂—, —CH(CH₃)— and —(CH₂)₂—.

[0038] When in the compounds of formula (1), L² and/or L³ is present asa linker atom or group it may be any divalent linking atom or group.Particular examples include —O— or —S— atoms or —C(O)—, —C(O)O—, ;—OC(O)—, —C(S)—, —S(O)—, —S(O)₂—, —NR¹¹— [where R¹¹ is a hydrogen atomor an optionally substituted alkyl group], —CON(R¹¹), —OC(O)N(R¹¹)—,—CSN(R¹¹)—, —N(R¹¹)CO—, —N(R¹¹)C(O)O—; —N(R¹¹)CS—, —S(O)₂N(R¹¹)—,—N(R¹¹)S(O)₂—, —N(R¹¹)CON(R¹¹)—, —N(R¹¹)CSN(R¹¹)—, or —N(R¹¹)SO₂N(R¹¹)—groups. Where the linker group contains two R¹¹ substituents, these maybe the same or different.

[0039] When R⁷, R⁸, R⁹, R¹⁰ and/or R¹¹ in the compounds of formula (1)is an alkyl group it may be a straight or branched C₁₋₆ alkyl group,e.g. a C₁₋₃ alkyl group such as a methyl or ethyl group. Optionalsubstituents which may be present on such groups include for exampleone, two or three substituents which may be the same or differentselected from halogen atoms, for example fluorine, chlorine, bromine oriodine atoms, or hydroxy or C₁₋₆ alkoxy e.g. methoxy or ethoxy groups.

[0040] When Alk³ is present in the compounds of formula (1) as analiphatic or heteroaliphatic chain it may be for example any of C¹-C¹⁰aliphatic or heteroaliphatic chains.

[0041] When Alk³ is present in compounds of formula (1) as an optionallysubstituted aliphatic chain it may be an optionally substituted C₁₋₁₀aliphatic chain. Particular examples include optionally substitutedstraight or branched chain C₁₋₆ alkyl, C₂₋₆ alkenyl, or C₂₋₆ alkynylchains.

[0042] Heteroaliphatic chains represented by Alk³ include the aliphaticchains just described but with each chain additionally containing one,two, three or four heteroatoms or heteroatom-containing groups.Particular heteroatoms or groups include atoms or groups L⁴ where L⁴ isas defined above for L¹ when L¹ is a linker atom or group. Each L⁴ atomor group may interrupt the aliphatic chain, or may be positioned at itsterminal carbon atom to connect the chain to an adjoining atom or group.

[0043] Particular examples of aliphatic chains represented by Alk¹include optionally substituted —CH₂—, —CH₂CH₂—, —CH(CH₃)—, —C(CH₃)₂—,—(CH₂)₂CH₂—, —CH(CH₃)CH₂—, —(CH₂)₃CH₂—, —CH(CH₃)CH₂CH₂—,—CH₂CH(CH₃)CH₂—, —C(CH₃)₂CH₂—, —(CH₂)₄CH₂—, —(CH₂)₅CH₂—, —CHCH—,—CHCHCH₂—, —CH₂CHCH—, CHCHCH₂CH₂—, —CH₂CHCHCH₂—, —(CH₂)₂CHCH—, —CC—,—CCCH₂—, —CH₂CC—, —CCCH₂CH₂—, —CH₂CCCH₂—, or —(CH₂)₂CC— chains. Whereappropriate each of said chains may be optionally interrupted by one ortwo atoms and/or groups L⁴ to form an optionally substitutedheteroaliphatic chain. Particular examples include optionallysubstituted -L⁴CH₂—, —CH₂L⁴CH₂—, -L⁴(CH₂)₂—, —CH₂L⁴(CH₂)₂—,—(CH₂)₂L⁴CH₂—, -L⁴(CH₂)₃— and —(CH₂)₂L⁴(CH₂)₂— chains. The optionalsubstituents which may be present on aliphatic or heteroaliphatic chainsrepresented by Alk¹ include one, two, three or more substituents whereeach substituent may be the same or different and is selected fromhalogen atoms, e.g. fluorine, chlorine, bromine or iodine atoms, or C₁₋₆alkoxy, e.g. methoxy or ethoxy, thiol, C₁₋₆ alkylthio e.g. methylthio orethylthio, amino or substituted amino groups. Substituted amino groupsinclude —NHR¹² and —N(R¹²)₂ groups where R¹² is an optionallysubstituted straight or branched alkyl group as defined below for R¹¹.Where two R¹² groups are present these may be the same or different.Particular examples of substituted chains represented by Alk¹ includethose specific chains just described substituted by one, two, or threehalogen atoms such as fluorine atoms, for example chains of the type—CH(CF₃)—, —C(CF₃)₂—, —CH₂CH(CF₃)—, —CH₂C(CF₃)₂—, —CH(CF₃)— and—C(CF₃)₂CH₂—.

[0044] Halogen atoms represented by R⁷ in compounds of the inventioninclude fluorine, chlorine, bromine, or iodine atoms.

[0045] Examples of the substituents represented by R⁴ and R¹ incompounds of formula (I) include atoms or groups -L²Alk³L³R⁷, -L²Alk³R⁷,-L²R⁷, -Alk³R⁷ and —R⁷ wherein L², Alk³, L³ and R⁷ are as defined above.Particular examples of such substituents include -L²CH₂L³R⁷,-L²CH(CH₃)L³R⁷, -L²CH(CH₂)₂L³R⁷, -L²CH₂R⁷, -L²CH(CH₃)R⁷, -L²(CH₂)₂R⁷,—CH₂R⁷, —CH(CH₃)R⁷ and —(CH₂)₂R⁷ groups.

[0046] Thus each of R⁴ and R⁵ in compounds of the invention may be forexample a hydrogen atom, a halogen atom, e.g. a fluorine, chlorine,bromine or iodine atom, or a C₁₋₆alkyl, e.g. methyl, ethyl, n-propyl,i-propyl, n-butyl or t-butyl, C₁₋₆ alkylamino, e.g. methylamino orethylamino, C₁₋₆ hydroxyalkyl, e.g. hydroxymethyl or hydroxyethyl,carboxy C₁₋₆ alkyl, e.g. carboxyethyl, C₁₋₆ alkylthio e.g. methylthio orethylthio, carboxy C₁₋₆ alkylthio, e.g. carboxymethylthio,2-carboxyethylthio or 3-carboxypropylthio, C₁₋₆ alkoxy, e.g. methoxy orethoxy, C₆₋₁₂ aryl C₁₋₆ alkyloxy e.g. benzyloxy, hydroxy C₁₋₆ alkoxy,e.g. 2-hydroxyethoxy, halo C₁₋₆ alkyl, e.g., trifluoromethyl, halo C₁₋₆alkoxy, e.g. trifluoromethoxy, C₁₋₆ alkylamino, e.g. methylamino orethylamino, amino (—NH₂), amino C₁₋₆ alkyl, e.g. aminomethyl oraminoethyl, C₁₋₆ dialkylamino, e.g. dimethylamino or diethylamino, C₁₋₆alkylaminoC₁₋₆ alkyl, e.g. ethylaminoethyl, C₁₋₆ dialkylamino C₁₋₆alkyl, e.g. diethylaminoethyl, amino C₁₋₆ alkoxy, e.g., aminoethoxy,C₁₋₆ alkylamino C₁₋₆ alkoxy, e.g. methylaminoethoxy, C₁₋₆ dialkylaminoC₁₋₆ alkoxy, e.g. dimethylaminoethoxy, diethylaminoethoxy,diisopropylaminoethoxy, or dimethylaminopropoxy, nitro, cyano, amidino,hydroxyl (—OH), formyl [HC(O)—], carboxyl (—CO₂H), —CO₂Alk⁵ [where Alk⁵is as defined below], C₁₋₆ alkanoyl e.g. acetyl, thiol (—SH),thioC₁₋₆alkyl, e.g., thiomethyl or thioethyl, thio C₁₋₆ alkyl C₆₋₁₂aryl, e.g. thiobenzyl, sulphonyl (—SO₃H), C₁₋₆ alkylsulphinyl, e.g.,methylsulphinyl, C₁₋₆ alkylsulphonyl, e.g. methylsulphonyl,aminosulphonyl (—SO₂ NH₂), C₁₋₆ alkylaminosulphonyl, e.g.methylaminosulphonyl or ethylaminosulphonyl, C₁₋₆ dialkylaminosulphonyl,e.g. dimethylaminosulphonyl or diethylaminosulphonyl,phenylaminosulphonyl, carboxamido (—CONH₂), C₁₋₆ alkylaminocarbonyl,e.g. methylaminocarbonyl or ethyl aminocarbonyl, C₁₋₆dialkylaminocarbonyl, e.g., dimethylaminocarbonyl ordiethylaminocarbonyl, amino C₁₋₆ alkylaminocarbonyl, e.g.aminoethylamino-carbonyl, C₁₋₆ dialkylamino C₁₋₆ alkylaminocarbonyl,e.g., diethylaminoethylaminocarbonyl, aminocarbonylamino, C₁₋₆alkylaminocarbony-lamino, e.g., methyl-aminocarbonylamino orethylaminocarbonylamino, C₁₋₆ dialkylaminocarbonyl-amino, e.g.,dimethylaminocarbonylamino or diethylaminocarbonylamino, C₁₋₆alkylaminocabonylC₁₋₆ alkylamino, e.g. methylaminocarbonylmethylamino,aminothiocarbonylamino, C₁₋₆alkylaminothiocarbonylamino, e.g.methylaminothiocarbonylamino or ethylaminothiocarbonylamino, C₁₋₆dialkylaminothiocarbonylamino, e.g. dimethylaminothiocarbonylamino ordiethylaminothiocarbonylamino, C₁₋₆ alkylaminothiocarbonyl C₁₋₆alkylamino, e.g. ethylaminothiocarbonylmethylamino, C₁₋₆alkylsulphonylamino, e.g. methylsulphonylamino or ethyl sulphonylamino,C₁₋₆ dialkylsulphonylamino, e.g. dimethylsulphonylamino ordiethylsulphonylamino, aminosulphonylamino (—NHSO₂NH₂), C₁₋₆alkylaminosulphonylamino, e.g. methylaminosulphonylamino orethylaminosulphonylamino, C₁₋₆ dialkylaminosulphonylamino, e.g.dimethylaminosulphonylamino or diethylaminosulphonylamino, C₁₋₆alkanoylamino, e.g. acetylamino, aminoC₁₋₆ alkanoylamino e.g.aminoacetylamino, C₁₋₆ dialkylaminoC₁₋₆ alkanoylamino, e.g.dimethylaminoacethylamino, C₁₋₆ alkanoylamino C₁₋₆ alkyl, e.g. acetylaminomethyl, C₁₋₆ alkanoylamino C₁₋₆ alkylamino, e.g.acetamidoethylamino, C₁₋₆ alkoxycarbonylamino, e.g.,methoxycarbonylamino, ethoxycarbonylamino or t-butoxycarbonylaminogroup.

[0047] Aromatc groups represented by the group Ar in compounds of theinvention include, for example, monocyclic or bicyclic fused ring C₆₋₁₂aromatic groups, such as phenyl, 1- or 2-naphthyl, 1- or2-tetrahydronaphthyl, indanyl or indenyl groups. Aromatic groupsrepresented by the group Ar may be optionally substituted by one, two,three or more R¹³ atoms or groups as defined below.

[0048] Heteroaromatic groups represented by the group Ar in thecompounds of the invention include for example C₁₋₉ heteroaromaticgroups containing for example one, two, three or four heteroatomsselected from oxygen, sulphur or nitrogen atoms. In general, theheteroaromatic groups may be for example monocyclic or bicyclic fusedring heteroaromatic groups. Monocyclic heteroaromatic groups include forexample five- or six-membered heteroaromatic groups containing one, two,three or four heteroatoms selected from oxygen, sulphur or nitrogenatoms. Bicyclic heteroaromatic groups include for example eight- tothirteen-membered fused-ring heteroaromatic groups containing one, twoor more heteroatoms selected from oxygen, sulphur or nitrogen atoms.

[0049] Particular examples of heteroaromatic groups of these typesinclude pyrrolyl, furyl, thienyl, imidazolyl, N—C₁₋₆ alkylimidazolyl,oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl,1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl,1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,3,4-thiadiazole, pyridyl,pyrimidinyl, pyridazinyl, pyrazinyl, 1,3,5-triazinyl, 1,2,4-triazinyl;1,2,3-triazinyl, benzofuryl, [2,3-dihydro]benzofuryl, benzothienyl,benzotriazolyl, indolyl, isoindolyl, benzimidazolyl,imidazo[1,2-a]pyridyl, benzothiazolyl, benzoxazolyl, benzopyranyl,[3,4-dihydro]benzopyranyl, quinazolinyl, qunoxalinyl, naphthyridinyl,pyrido[3,4-b]pyridyl, pyrido[3,2-b]pyridyl, pyrido[4,3-b]-pyridyl,quinolinyl, isoquinolinyl, tetrazolyl, 5,6,7,8-tetrahydroquinolinyl,5,6,7,8-tetrahydroisoquinolinyl, and imidyl, e.g. succinimidyl,phthalimidyl, or naphthalimidyl such as 1,8-naphthalimidyl.

[0050] Optional substituents which may be present on the aromatic orheteroaromatic groups represented by Ar include one, two, three or moresubstituents, each selected from an atom or group R¹³ in which R¹³ isR^(13a) or -Alk⁴(R^(13a))_(m), where R^(13a) is a halogen atom, or anamino (—NH₂), substituted amino, nitro, cyano, amidino, hydroxyl (—OH),substituted hydroxyl, formyl, carboxyl (—CO₂H), esterified carboxyl,thiol (—SH), substituted thiol, —COR¹⁴ [where R¹⁴ is an-Alk³(R^(13a))_(n), aryl or heteroaryl group], —CSR¹⁴, —SO₃H,—SO₂R¹⁴—SO₂NH₂, —SO₂NHR⁴, —SO₂N(R⁴)₂, —CONH₂, —CSNH₂, —CONHR⁴, —CSNHR¹⁴,—CON[R¹⁴]₂, —CSN(R¹⁴)₂, —N(R¹²)SO₂R¹⁴, —N(SO₂R¹⁴)₂, —NH(R¹¹)SO₂NH₂,—N(R¹¹)SO₂NHR⁴, —N(R¹¹)SO₂N(R⁴)₂, —N(R¹¹)COR¹⁴, —N(R¹¹)CON(R¹⁴)₂,—N(R¹¹)CSN(R⁴)₂, —N(R¹¹)CSR⁴, —N(R¹¹)C(O)OR¹⁴, —SO²NHet¹ [where —NHet¹is an optionally substituted C₅₋₇cyclicamino group optionally containingone or more other —O— or —S— atoms or —N(R¹¹)—, —C(O)— or —C(S)groups],—CONHet¹, —CSNHet¹, —N(R¹¹)SO₂NHet¹, —N(R¹¹)CONHet¹, —N(R¹¹)CSNHet¹,-Het², [where Het² is an optionally substituted monocyclic C₅₋₇carbocyclic group optionally containing one or more —O— or —S— atoms or—N(R¹¹)—, —C(O)— or —C(S)— groups]—SO₂N(R¹¹)Het², —CON(R¹¹)Het²,—CSN(R¹¹)Het², —N(R¹¹)CON(R¹¹)Het², —N(R¹¹)CSN(R¹¹)Het², aryl orheteroaryl group; Alk⁴ is a straight or branched C₁₋₆ alkylene, C₂₋₆alkenylene or C₂₋₆ alkynylene chain, optionally interrupted by one, twoor three —O— or —S— atoms or —S(O)_(n) [where n is an integer 1 or 2] or—N(R¹⁵)— groups [where R¹⁵ is a hydrogen atom or C₁₋₆alkyl, e.g. methylor ethyl group]; and m is zero or an integer 1, 2 or 3. It will beappreciated that when two R¹¹ or R¹⁴ groups are present in one of theabove substituents, the R¹¹ or R¹⁴ groups may be the same or different.

[0051] When in the group -Alk⁴(R^(13a))_(n) m is an integer 1, 2 or 3,it is to be understood that the substituent or substituents R^(13a) maybe present on any suitable carbon atom in -Alk⁴. Where more than oneR^(13a) substituent is present these may be the same or different andmay be present on the same or different atom in -Alk⁴. Clearly, when mis zero and no substituent R^(13a) is present the alkylene, alkenyleneor alkynylene chain represented by Alk⁴ becomes an alkyl, alkenyl oralkynyl group.

[0052] When R^(13a) is a substituted amino group it may be for example agroup —NHR¹⁴ [where R¹⁴ is as defined above] or a group —N(R¹⁴)₂ whereineach R¹⁴ group is the same or different.

[0053] When R^(13a) is a halogen atom it may be for example a fluorine,chlorine, bromine, or iodine atom.

[0054] When R^(13a) is a substituted hydroxyl or substituted thiol groupit may be for example a group —OR¹⁴ or a —SR¹⁴ or —SC(═NH)NH₂ grouprespectively.

[0055] Esterified carboxyl groups represented by the group R^(13a)include groups of formula —CO₂Alk⁵ wherein Alk⁵ is a straight orbranched, optionally substituted C₁₋₈ alkyl group such as a methyl,ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl or t-butyl group; aC₆₋₁₂ aryl C₁₋₈ alkyl group such as an optionally substituted benzyl,phenylethyl, phenylpropyl, 1-naphthylmethyl or 2-naphthylmethyl group; aC₆₋₁₂ aryl group such as an optionally substituted phenyl, 1-naphthyl or2-naphthyl group; a C₆₋₁₂ aryloxy C₁₋₈ alkyl group such as an optionallysubstituted phenyloxymethyl, phenyloxyethyl, 1-naphthyl-oxymethyl, or2-naphthyloxymethyl group; an optionally substituted C₁₋₈ alkanoyloxyC₁₋₈ alkyl group, such as a pivaloyloxymethyl, propionyloxyethyl orpropionyloxypropyl group; or a C₆₋₁₂ aroyloxy C₁₋₈ alkyl group such asan optionally substituted benzoyloxyethyl or benzoyloxypropyl group.Optional substituents present on the Alks group include R^(13a)substituents described above.

[0056] When Alk⁴ is present in or as a substituent it may be for examplea methylene, ethylene, n-propylene, i-propylene, n-butylene, i-butylene,sbutylene, t-butylene, ethenylene, 2-propenylene, 2-butenylene,3-butenylene, ethynylene, 2-propynylene, 2-butynylene or 3-butynylenechain, optionally interrupted by one, two, or three —O— or —S—, atoms or—S(O)—, —S(O— or —N(R¹²)— groups.

[0057] Aryl or heteroaryl groups represented by the groups R^(13a) orR¹⁴ include mono- or bicyclic optionally substituted C₆₋₁₂ aromatic orC₁₋₉ heteroaromatic groups as described above for the group Ar. Thearomatic and heteroaromatic groups may be attached to the remainder ofthe compound of formula (1) by any carbon or hetero, e.g. nitrogen atom,as appropriate.

[0058] When -NHet¹ or -Het² forms part of a substituent R¹³ each may befor example an optionally substituted pyrrolidinyl, pyrazolidinyl,piperazinyl, morpholinyl, thiomorpholinyl, piperidinyl or thiazolidinylgroup. Additionally Het² may represent for example, an optionallysubstituted cyclopentyl or cyclohexyl group. Optional substituents whichmay be present on -NHet¹ or -Het² include those R⁷ substituentsdescribed above.

[0059] Particularly useful atoms or groups represented by R¹³ includefluorine, chlorine, bromine or iodine atoms, or C₁₋₆ alkyl, e.g. methyl,ethyl, n-propyl, i-propyl, n-butyl or t-butyl, optionally substitutedphenyl, pyridyl, pyrimidinyl, pyrrolyl, furyl, thiazolyl, or thienyl,morpholinyl, thiomorpholinyl, piperazinyl, pyrrolidinyl, piperidinyl,C₁₋₆ alkylamino, e.g. methylamino or ethylamino, C₁₋₆ hydroxyalkyl, e.g.hydroxymethyl or hydroxyethyl, carboxyC₁₋₆ alkyl, e.g. carboxyethyl,C₁₋₆ alkylthio e.g. methylthio or ethylthio, carboxy C₁₋₆ alkylthio,e.g. carboxymethylthio, 2-carboxyethylthio or 3-carboxypropylthio, C₁₋₆alkoxy, e.g. methoxy or ethoxy, hydroxy C₁₋₆ alkoxy, e.g.2-hydroxyethoxy, optionally substituted phenoxy, pyridyloxy,thiazolyoxy, phenylthio or pyridylthio, C₅₋₇ cycloalkoxy, e.g.cyclopentyloxy, halo C₁₋₆ alkyl, e.g. trifluoromethyl, halo C₁₋₆ alkoxy,e.g. trifluoromethoxy, C₁₋₆ alkylamino, e.g. methylamino or ethylaminoor propylamino, optionally substituted C₆₋₁₂ aryl C₁₋₆ alkylamino, e.g.benzylamino, fluorobenzylamino or hydroxyphenylethylamino, amino (—NH₂),amino C₁₋₆ alkyl, e.g. aminomethyl or aminoethyl, C₁₋₆ dialkylamino,e.g. dimethylamino or diethylamino, amino C₁₋₆ alklamino e.g.aminomethylamino, aminoethylamino or aminopropylamino, Het¹ NC₁₋₆alkylamino e.g., morpholinopropylamino, C₁₋₆ alkylamino C₁₋₆ alkyl, e.g.ethylaminoethyl, C₁₋₆ dialkylamino C₁₋₆ alkyl, e.g. diethylaminoethyl,amino C₁₋₆ alkoxy, e.g. aminoethoxy, C₁₋₆ alkylamino C₁₋₆ alkoxy, e.g.methylaminoethoxy, C₁₋₆ dialkylamino C₁₋₆ alkoxy, e.g.dimethylaminoethoxy, diethylaminoethoxy, diisopropylaminoethoxy, ordimethylaminopropoxy, hydroxy C₁₋₆ alkylamino, e.g. hydroxyethylamino,hydroxypropylamino or hydroxybutylamino, imido, such as phthalimido ornaphthalimido, e.g. 1,8-naphthalimido, nitro, cyano, amidino, hydroxyl(—OH), formyl [HC(O)—], carboxyl (—CO₂H), —CO₂Alk⁵ [where Alk⁵ is asdefined above], C₁₋₆ alkanoyl e.g. acetyl, propyryl or butyryl,optionally substituted benzoyl, thiol (—SH), thioC₁₋₆alkyl, e.g.,thiomethyl or thioethyl, —SC(═NH)NH₂, sulphonyl (—SO₃H),C₁₋₆alkylsulphinyl, e.g. methylsulphinyl, ethylsulphinyl orpropylsulphinyl, C₁₋₆ alkylsulphonyl, e.g. methylsulphonyl,ethylsulphonyl, propylsulphonyl, hexylsulphonyl or isobutylsulphonyl,aminosulphonyl (—SO₂NH₂), C₁₋₆ alkylaminosulphonyl, e.g.methylaminosulphonyl, ethylaminosulphonyl or propylaminocsulphonyl, C₁₋₆dialkylaminosulphonyl, e.g. dimethylaminosulphonyl ordiethylaminosulphonyl, optionally substituted phenylaminosulphonyl,carboxamido (—CONH₂), C₁₋₆ alkylaminocarbonyl, e.g. methylaminocarbonyl,ethylaminocarbonyl or propylaminocarbonyl, C₁₋₆ dialkylaminocarbonyl,e.g. dimethylaminocarbonyl, diethylaminocarbonyl ordipropylaminocarbonyl, amino C₁₋₆ alkylaminocarbonyl, e.g.aminoethylaminocarbonyl, C₁₋₆ dialkylamino C₁₋₆ alkylaminocarbonyl, e.g.diethylaminoethylaminocarbonyl, aminocarbonylamino, C₁₋₆alkylaminocarbonylamino, e.g. methylaminocarbonylamino orethylaminocarbonylamino, C₁₋₆ dialkylaminocarbonylamino, e.g.dimethylaminocarbonylamino or diethylaminocarbonylamino, C₁₋₆alkylaminocabonyl C₁₋₆ alkylamino, e.g. methylaminocarbonylmethylamino,aminothiocarbonylamino, C₁₋₆ alkylaminothiocarbonylamino, e.g.methylaminothiocarbonylamino or ethylaminothiocarbonylamino, C₁₋₆dialkylaminothiocarbonylamino, e.g. dimethylaminothiocarbonylamino ordiethylaminothiocarbonylamino, C₁₋₆ alkylaminothiocarbonyl C₁₋₆alkylamino, e.g. ethylaminothiocarbonylmethylamino, —CONHC(═NH)NH₂, C₁₋₆alkylsufphonylamino, e.g. methylsulphonylamino or ethylsulphonylamino,C₁₋₆ dialkylsulphonylamino, e.g. dimethylsulphonylamino ordiethylsulphonylamino, optionally substituted phenylsulphonylamino,aminosulphonylamino (—NHSO₂NH₂), C₁₋₆ alkylaminosulphonylamino, e.g.methylaminosulphonylamino or ethylaminosulphonylamino, C₁₋₆dialkylaminosulphonylamino, e.g. dimethylaminosulphonylamino ordiethylaminosulphonylamino, optionally substitutedmorpholinesulphonylamino or morpholinesulphonyl C₁₋₆ alkyl-amino,optionally substituted phenylaminosulphonylamino, C₁₋₆ alkanoylamino,e.g. acetylamino, amino C₁₋₆ alkanoylamino e.g. aminoacetylamino, C₁₋₆dialkylamino C₁₋₆ alkanoylamino, e.g., dimethylaminoacetylamino, C₁₋₆alkanoylamino C₁₋₆ alkyl, e.g. acetylaminomethyl, C₁₋₆ alkanoylaminoC₁₋₆ alkylamino, e.g. acetamidoethylamino, C₁₋₆ alkoxycarbonylamino,e.g. methoxycarbonylamino, ethoxycarbonylamino or t-butoxycarbonylaminoor optionally substituted benzyloxy, pyridylmethoxy, thiazolylmethoxy,benzyloxycarbonylamino, benzyloxycarbonylamino C₁₋₆ alkyl e.g.benzyloxycarbonylaminoethyl, thiobenzyl, pyridylmethylthio orthiazolylmethylthio groups.

[0060] Where desired, two R¹³ substituents may be linked together toform a cyclic group such as a cyclic ether, e.g. a C₁₋₆ alkylenedioxygroup such as methylenedioxy or ethylenedioxy.

[0061] It will be appreciated that where two or more R¹³ substituentsare present, these need not necessarily be the same atoms and/or groups.In general, the substituent(s) may be present at any available ringposition in the 5 aromatic or heteroaromatic group represented by Ar.

[0062] The presence of certain substituents in the compounds of formulae(1) and (2) may enable salts of the compounds to be formed. Suitablesalts include pharmaceutically acceptable salts, for example acidaddition salts derived from inorganic or organic acids, and saltsderived from inorganic and organic bases.

[0063] Acid addition salts include hydrochlorides, hydrobromides,hydroiodides, alkylsulphonates, e.g. methanesulphonates,ethanesulphonates, or isothionates, arylsulphonates, e.g.p-toluenesulphonates, besylates or napsylates, phosphates, sulphates,hydrogen sulphates, acetates, trifluoroacetates, propionates, citrates,maleates, fumarates, malonates, succinates, lactates, oxalates,tartrates and benzoates.

[0064] Salts derived from inorganic or organic bases include alkalimetal salts such as sodium or potassium salts, alkaline earth metalsalts such as magnesium or calcium salts, and organic amine salts suchas morpholine, piperidine, dimethylamine or diethylamine salts.

[0065] Particularly useful salts of compounds according to the inventioninclude pharmaceutically acceptable salts, especially acid additionpharmaceutically acceptable salts.

[0066] R in the compounds of formulae (1) and (2) is preferably a —COHgroup.

[0067] In compounds of formulae (1) and (2), m is preferably 1 and Alk²is preferably —CH₂—.

[0068] R⁴ and R⁵ in the compounds of formulae (1) and (2) may be thesame or different and is each preferably a hydrogen or halogen atom oran alkyl, alkoxy, hydroxy, nitro, cyano or —NR⁸R⁹ group.

[0069] R⁶ and R^(a) in the compounds of formulae (1) and (2) is eachpreferably a hydrogen atom.

[0070] Particularly useful classes of compounds according to theinvention are those wherein Ar is an optionally substituted monocyclicaromatic or heteroaromatic group. One especially useful aromatic groupwhen represented by Ar is phenyl. Especially useful heteroaromaticgroups represented by Ar include optionally substituted monocyclicnitrogen containing heteroaromatic groups, particularly optionallysubstituted pyridyl, pyrimidinyl, pyridazinyl and triazinyl groups.Where the group is a triazinyl group it is preferably a 1,3,5 triazine.

[0071] Optional substituents which may be present on preferred Araromatic or heteroaromatic groups include for example one or twosubstituents selected from those R¹³ substituents described above.

[0072] Particularly useful R¹³ substituents of these types include ahalogen atom, especially fluorine or chlorine, morpholinyl,thiomorpholinyl, optionally substituted piperidinyl, especiallypiperidinyl or 4-carboxypiperidinyl, pyrrolidinyl, optionallysubstituted piperazinyl, especially t-butyloxycarbonylpiperazinyl, thioC₁₋₆ alkyl, especially thiomethyl, thioethyl or thiopropyl, optionallysubstituted thiobenzyl, especially thiobenzyl, halo C₁₋₆ alkyl,especially trifluoromethyl, C₁₋₆ alkyloxy, especially methoxy, ethoxy orpropoxy, optionally substituted benzyloxy, especially benzyloxy, haloC₁₋₆ alkoxy, especially trifluoromethoxy and difluoromethoxy, C₁₋₆alkylamino, especially methylamino, ethylamino or propylamino, C₁₋₆dialkylamino, especially dimethylamino or diethylamino, optionallysubstituted C₆₋₁₂ aryl C₁₋₆ alkylamino, especially benzylamino,4-substituted benzyl, especially 4-fluorobenzylamino or4-hydroxyphenylethylamino, aminoalkylamino, especially3-aminopropylamino, Het¹ N(C₁₋₆ alkylamino), especially3-morpholinopropylamino, optionally substituted phenoxy, especiallyphenoxy, hydroxy C₁₋₆ alkylamino, especially 2-hydroxyethylamino,3-hydroxypropylamino and 3-hydroxybutylamino, nitro, carboxyl, —CO₂Alk⁵[where Alk⁵ is as defined above], especially carboxymethyl andcarboxyethyl, carboxamido, C₁₋₆ alkylaminocarbonyl, especiallymethylaminocarbonyl, ethylaminocarbonyl and propylaminocarbonyl, C₁₋₆dialkylaminocarbonyl, especially dimehylaminocarbonyl,diethylaminocarbonyl or dipropylaminocarbonyl, C₁₋₆ alkanoyl, especiallyacetyl, propyryl or butyryl, optionally substituted benzoyl, especiallybenzoyl, C₁₋₆ alkylsulphinyl, especially methylsulphinyl, ethylsulphinylor propylsulphinyl, Cl-alkylsulphonyl, especially methylsulphonyl,ethylsulphonyl, propylsulphonyl, hexylsulphonyl or isobutylsulphonyl,C₁₋₆ alkylaminosulphonyl, especially ethylaminosulfonyl orpropylamino-sulphonyl, C₁₋₆ dialkylaminosulphonyl, especiallydiethylaminosulphonyl, C₁₋₆ alkylaminocarbonyl, especiallymethylaminocarbonyl, ethylaminocarbonyl or propylaminocarbonyl, C₁₋₆dialkylaminocarbonyl, especially dimethylaminocarbonyl ordiethylaminocarbonyl.

[0073] Particularly useful Alk⁴ groups when present in compounds of theinvention include —CH₂—, —CH₂CH₂—, —(CH₂)₂CH₂—, —CH(CH₃)CH₂— and—(CH₂)₃CH₂— groups.

[0074] Particularly useful compounds of the invention include:

[0075] S-3-[4-(N,N-dimethylaminocarbonyloxy)phenyl]-2-(6propylsulphinylpyrimidin-4-ylamino)propanoic acid;

[0076] S-3-[4-(N,N-dimethylaminocarbonyloxy)phenyl]-2-(6diethylaminosulphonylpyrimidin-4-ylamino)propanoic acid; and

[0077]S-3-[4-(N-morpholinocarbonyloxy)phenyl]-2-(6-diethylaminosulphonylpyrimidin-4-ylamino)propanoicacid;

[0078] and the salts, solvates, hydrates and N-oxides thereof.

[0079] Compounds according to the invention are potent and selectiveinhibitors of α4 integrins. The ability of the compounds to act in thisway may be simply determined by employing tests such as those describedin the Examples hereinafter.

[0080] The compounds are of use in modulating cell adhesion and inparticular are of use in the prophylaxis and treatment of diseases ordisorders involving inflammation in which the extravasation ofleukocytes plays a role and the invention extends to such a use and tothe use of the compounds for the manufacture of a medicament fortreating such diseases or disorders.

[0081] Diseases or disorders of this type include inflammatory arthritissuch as rheumatoid arthritis vasculitis or polydermatomyositis, multiplesclerosis, allograft rejection, diabetes, inflammatory dermatoses suchas psoriasis or dermatitis, asthma and inflammatory bowel disease.

[0082] For the prophylaxis or treatment of disease the compoundsaccording to the invention may be administered as pharmaceuticalcompositions, and according to a further aspect of the invention weprovide a pharmaceutical composition which comprises a compound offormula (1) together with one or more pharmaceutically acceptablecarriers, excipients or diluents.

[0083] Pharmaceutical compositions according to the invention may take aform suitable for oral, buccal, parenteral, nasal, topical or rectaladministration, or a form suitable for administration by inhalation orinsufflation.

[0084] For oral administration, the pharmaceutical compositions may takethe form of, for example, tablets, lozenges or capsules prepared byconventional means with pharmaceutically acceptable excipients such asbinding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidoneor hydroxypropyl methylcellulose); fillers (e.g. lactose,microcrystalline cellulose or calcium hydrogen phosphate); lubricants(e.g. magnesium stearate, talc or silica); disintegrants (e.g. potatostarch or sodium glycollate); or wetting agents (e.g. sodium laurylsulphate). The tablets may be coated by methods well known in the art.Liquid preparations for oral administration may take the form of, forexample, solutions, syrups or suspensions, or they may be presented as adry product for constitution with water or other suitable vehicle beforeuse. Such liquid preparations may be prepared by conventional means withpharmaceutically acceptable additives such as suspending agents,emulsifying agents, non-aqueous vehicles and preservatives. Thepreparations may also contain buffer salts, flavouring, colouring andsweetening agents as appropriate.

[0085] Preparations for oral administration may be suitably formulatedto give controlled release of the active compound.

[0086] For buccal administration the compositions may take the form oftablets or lozenges formulated in conventional manner.

[0087] The compounds for formulae (1) and (2) may be formulated forparenteral administration by injection e.g. by bolus injection orinfusion. Formulations for injection may be presented in unit dosageform, e.g. in glass ampoule or multi dose containers, e.g. glass vials.The compositions for injection may take such forms as suspensions,solutions or emulsions in oily or aqueous vehicles, and may containformulatory agents such as suspending, stabilising, preserving and/ordispersing agents. Alternatively, the active ingredient may be in powderform for constitution with a suitable vehicle, e.g. sterile pyrogen-freewater, before use.

[0088] In addition to the formulations described above, the compounds offormulae (1) and (2) may also be formulated as a depot preparation. Suchlong acting formulations may be administered by implantation or byintramuscular injection.

[0089] For nasal administration or administration by inhalation, thecompounds for use according to the present invention are convenientlydelivered in the form of an aerosol spray presentation for pressurisedpacks or a nebuliser, with the use of suitable propellant, e.g.dichlorodifluoromethane, trichloro-fluoromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas ormixture of gases.

[0090] The compositions may, if desired, be presented in a pack ordispenser device which may contain one or more unit dosage formscontaining the active ingredient. The pack or dispensing device may beaccompanied by instructions for administration.

[0091] The quantity of a compound of the invention required for theprophylaxis or treatment of a particular condition will vary dependingon the compound chosen, and the condition of the patient to be treated.In general, however, daily dosages may range from around 100 ng/kg to100 mg/kg e.g. around 0.01 mg/kg to 40 mg/kg body weight for oral orbuccal administration, from around 10 ng/kg to 50 mg/kg body weight forparenteral administration and around 0.05 mg to around 1000 mg e.g.around 0.5 mg to around 1000 mg for nasal administration oradministration by inhalation or insufflation.

DETAILED DESCRIPTION OF THE INVENTION

[0092] As used herein, the following terms have the following meaningsunless more limited definitions are used:

[0093] As used herein, “alkyl” refers to alkyl groups preferably havingfrom 1 to 10 carbon atoms and more preferably 1 to 6 carbon atoms. Thisterm is exemplified by groups such as methyl, t-butyl, n-heptyl, octyland the like.

[0094] “Substituted alkyl” refers to an alkyl group, preferably of from1 to 10 carbon atoms, having from 1 to 5 substituents selected from thegroup consisting of alkoxy, substituted alkoxy, acyl, acylamino,thiocarbonylamino, acyloxy, amino, amidino, alkyl amidino, thioamidino,aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy,aryl, substituted aryl, aryloxy, substituted aryloxy, aryloxyaryl,substituted aryloxyaryl, cyano, halogen, hydroxyl, nitro, carboxyl,carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl,carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substitutedaryl, carboxylheteroaryl, carboxyl-substituted heteroaryl,carboxylheterocyclic, carboxyl-substituted heterocyclic, cycloalkyl,substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl,substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl,substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl,thioheterocyclic, substituted thioheterocyclic, heteroaryl, substitutedheteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy,substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy,heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino,oxythiocarbonylamino, —OS(O)₂-alkyl, —OS(O)₂-substituted alkyl,—OS(O)₂-aryl, —OS(O)₂-substituted aryl, —OS(O)₂-heteroaryl,—OS(O)₂-substituted heteroaryl, —OS(O)₂-heterocyclic,—OS(O)₂-substituted heterocyclic, —OSO₂—NRR where R is hydrogen oralkyl, —NRS(O)₂-alkyl, —NRS(O)₂-substituted alkyl, —NRS(O)₂-aryl,—NRS(O)₂-substituted aryl, —NRS(O)₂-heteroaryl, —NRS(O)₂-substitutedheteroaryl, —NRS(O)₂-heterocyclic, —NRS(O)₂-substituted heterocyclic,—NRS(O)₂—NR-alkyl, —NRS(O)₂—NR-substituted alkyl, —NRS(O)₂—NR-aryl,—NRS(O)₂—NR-substituted aryl, —NRS(O)₂—NR-heteroaryl,—NRS(O)₂—NR-substituted heteroaryl, —NRS(O)₂—NR-heterocyclic,—NRS(O)₂—NR-substituted heterocyclic where R is hydrogen or alkyl, mono-and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- anddi-arylamino, mono- and di-substituted arylamino, mono- anddi-heteroarylamino, mono- and di-substituted heteroarylamino, mono- anddi-heterocyclic amino, mono- and di-substituted heterocyclic amino,unsymmetric di-substituted amines having different substituents selectedfrom alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, heterocyclic and substituted heterocyclic andsubstituted alkyl groups having amino groups blocked by conventionalblocking groups such as Boc, Cbz, formyl, and the like oralkyl/substituted alkyl groups substituted with —SO₂-alkyl,—SO₂-substituted alkyl, —SO₂-alkenyl, —SO₂— substituted alkenyl,—SO₂-cycloalkyl, —SO₂-substituted cycloalkyl, —SO₂-aryl,—SO₂-substituted aryl, —SO₂-heteroaryl, —SO₂-substituted heteroaryl,—SO₂-heterocyclic, —SO₂-substituted heterocyclic and —SO₂NRR where R ishydrogen or alkyl.

[0095] “Alkoxy” refers to the group “alkyl-O-” which includes, by way ofexample, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy,sec-butoxy, n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, and the like.

[0096] “Substituted alkoxy” refers to the group “substituted alkyl-O—”.

[0097] “Alkenoxy” refers to the group “alkenyl-O—”.

[0098] “Substituted alkenoxy” refers to the group “substitutedalkenyl-O—”.

[0099] “Acyl” refers to the groups H—C(O)—, alkyl-C(O)—, substitutedalkyl-C(O)—, alkenyl-C(O)—, substituted alkenyl-C(O)—, alkynyl-C(O)—,substituted alkynyl-C(O)— cycloalkyl-C(O)—, substitutedcycloalkyl-C(O)—, aryl-C(O)—, substituted aryl-C(O)—, heteroaryl-C(O)—,substituted heteroaryl-C(O), heterocyclic-C(O)—, and substitutedheterocyclic-C(O)— wherein alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic and substituted heterocyclic are as definedherein.

[0100] “Acylamino” refers to the group —C(O)NRR where each R isindependently selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl,heteroaryl, substituted heteroaryl, heterocyclic, substitutedheterocyclic and where each R is joined to form together with thenitrogen atom a heterocyclic or substituted heterocyclic ring whereinalkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic andsubstituted heterocyclic are as defined herein.

[0101] “Thiocarbonylamino” refers to the group —C(S)NRR where each R isindependently selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl,heteroaryl, substituted heteroaryl, heterocyclic, substitutedheterocyclic and where each R is joined to form, together with thenitrogen atom a heterocyclic or substituted heterocyclic ring whereinalkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic andsubstituted heterocyclic are as defined herein.

[0102] “Acyloxy” refers to the groups alkyl-C(O)O—, substitutedalkyl-C(O)O—, alkenyl-C(O)O—, substituted alkenyl-C(O)O—,alkynyl-C(O)O—, substituted alkynyl-C(O)O—, aryl-C(O)O—, substitutedaryl-C(O)O—, cycloalkyl-C(O)O—, substituted cycloalkyl-C(O)O—,heteroaryl-C(O)O—, substituted heteroaryl-C(O)O—, heterocyclic-C(O)O—,and substituted heterocyclic-C(O)O— wherein alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic and substituted heterocyclic are as definedherein.

[0103] “Oxysulfonyl” refers to the groups alkyl-SO₂O—, substitutedalkyl-SO₂O—, alkenyl-SO₂O—, substituted alkenyl-SO₂O—, alkynyl-SO₂O—,substituted alkynyl-SO₂O—, aryl-SO₂O—, substituted aryl-SO₂O—,cycloalkyl-SO₂O—, substituted cycloalkyl-SO₂O—, heteroaryl-SO₂O—,substituted heteroaryl-SO₂O—, heterocyclic-SO₂O—, and substitutedheterocyclic-SO₂O— wherein alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic and substituted heterocyclic are as definedherein.

[0104] “Alkenyl” refers to alkenyl group preferably having from 2 to 10carbon atoms and more preferably 2 to 6 carbon atoms and having at least1 and preferably from 1-2 sites of alkenyl unsaturation.

[0105] “Substituted alkenyl” refers to alkenyl groups having from 1 to 5substituents selected from the group consisting of alkoxy, substitutedalkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino, amidino,alkylamidino, thioamidino, aminoacyl, aminocarbonylamino,aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl,aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl,halogen, hydroxyl, cyano, nitro, carboxyl, carboxylalkyl,carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substitutedcycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl,carboxyl-substituted heteroaryl, carboxylheterocyclic,carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl,guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl,thioaryl, substituted thioaryl, thiocycloalkyl, substitutedthiocycloalkyl, thioheteroaryl, substituted thioheteroaryl,thioheterocyclic, substituted thioheterocyclic, heteroaryl, substitutedheteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy,substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy,heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino,oxythiocarbonylamino, —OS(O)₂-alkyl, —OS(O)₂-substituted alkyl,—OS(O)₂-aryl, —OS(O)₂-substituted aryl, —OS(O)₂-heteroaryl,—OS(O)₂-substituted heteroaryl, —OS(O)₂-heterocyclic,—OS(O)₂-substituted heterocyclic, —OSO₂—NRR where R is hydrogen oralkyl, —NRS(O)₂-alkyl, —NRS(O)₂-substituted alkyl, —NRS(O)₂-aryl,—NRS(O)₂-substituted aryl, —NRS(O)₂-heteroaryl, —NRS(O)₂-substitutedheteroaryl, —NRS(O)₂-heterocyclic, —NRS(O)₂-substituted heterocyclic,—NRS(O)₂—NR-alkyl, —NRS(O)₂—NR-substituted alkyl, —NRS(O)₂—NR-aryl,—NRS(O)₂—NR-substituted aryl, —NRS(O)₂—NR-heteroaryl,—NRS(O)₂—NR-substituted heteroaryl, —NRS(O)₂—NR-heterocyclic,—NRS(O)₂—NR-substituted heterocyclic where R is hydrogen or alkyl, mono-and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- anddi-arylamino, mono- and di-substituted arylamino, mono- anddi-heteroarylamino, mono- and di-substituted heteroarylamino, mono- anddi-heterocyclic amino, mono- and di-substituted heterocyclic amino,unsymmetric di-substituted amines having different substituents selectedfrom alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, heterocyclic and substituted heterocyclic andsubstituted alkenyl groups having amino groups blocked by conventionalblocking groups such as Boc, Cbz, formyl, and the like oralkenyl/substituted alkenyl groups substituted with —SO₂-alkyl,—SO₂-substituted alkyl, —SO₂-alkenyl, —SO₂-substituted alkenyl,—SO₂-cycloalkyl, —SO₂-substituted cycloalkyl, —SO₂-aryl,—SO₂-substituted aryl, —SO₂-heteroaryl, —SO₂-substituted heteroaryl,—SO₂-heterocyclic, —SO₂-substituted heterocyclic and —SO₂NRR where R ishydrogen or alkyl.

[0106] “Alkynyl” refers to alkynyl group preferably having from 2 to 10carbon atoms and more preferably 3 to 6 carbon atoms and having at least1 and preferably from 1-2 sites of alkynyl unsaturation.

[0107] “Substituted alkynyl” refers to alkynyl groups having from 1 to 5substituents selected from the group consisting of alkoxy, substitutedalkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino, amidino,alkylamidino, thioamidino, aminoacyl, aminocarbonylamino,aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl,aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl,halogen, hydroxyl, cyano, nitro, carboxyl, carboxylalkyl,carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substitutedcycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl,carboxyl-substituted heteroaryl, carboxylheterocyclic,carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl,guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl,thioaryl, substituted thioaryl, thiocycloalkyl, substitutedthiocycloalkyl, thioheteroaryl, substituted thioheteroaryl,thioheterocyclic, substituted thioheterocyclic, heteroaryl, substitutedheteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy,substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy,heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino,oxythiocarbonylamino, —OS(O)₂-alkyl, —OS(O)₂-substituted alkyl,—OS(O)₂-aryl, —OS(O)₂-substituted aryl, —OS(O)₂-heteroaryl,—OS(O)₂-substituted heteroaryl, —OS(O)₂-heterocyclic,—OS(O)₂-substituted heterocyclic, —OSO₂—NRR where R is hydrogen oralkyl, —NRS(O-alkyl, —NRS(O)₂-substituted alkyl, —NRS(O)₂-aryl,—NRS(O)₂-substituted aryl, —NRS(O)₂-heteroaryl, —NRS(O)₂-substitutedheteroaryl, —NRS(O)₂-heterocyclic, —NRS(O)₂-substituted heterocyclic,—NRS(O)₂—NR-alkyl, —NRS(O)₂—NR-substituted alkyl, —NRS(O)₂—NR-aryl,—NRS(O)₂—NR-substituted aryl, —NRS(O)₂—NR-heteroaryl,—NRS(O)₂—NR-substituted heteroaryl, —NRS(O)₂—NR-heterocyclic,—NRS(O)₂—NR-substituted heterocyclic where R is hydrogen or alkyl, mono-and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- anddi-arylamino, mono- and di-substituted arylamino, mono- anddi-heteroarylamino, mono- and di-substituted heteroarylamino, mono- anddi-hcterocyclic amino, mono- and di-substituted heterocyclic amino,unsymmetric di-substituted amines having different substituents selectedfrom alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, heterocyclic and substituted heterocyclic andsubstituted alkynyl groups having amino groups blocked by conventionalblocking groups such as Boc, Cbz, formyl, and the like oralkynyl/substituted alkynyl groups substituted with —SO₂-alkyl,—SO₂-substituted alkyl, —SO₂-alkenyl, —SO₂-substituted alkenyl,—SO₂-cycloalkyl, —SO₂-substituted cycloalkyl, —SO₂-aryl,—SO₂-substituted aryl, —SO₂-heteroaryl, —SO₂-substituted heteroaryl,—SO₂-hetero-cyclic, —SO₂-substituted heterocyclic and —SO₂NRR where R ishydrogen or alkyl.

[0108] “Amidino” refers to the group H₂NC(═NH)— and the term“alkylamidino” refers to compounds having 1 to 3 alkyl groups (e.g.,alkylHNC(═NH)—).

[0109] “Thioamidino” refers to the group RSC(═NH)— where R is hydrogenor alkyl.

[0110] “Amino” refers to the group —NH₂.

[0111] “Substituted amino” refers to the group —NRR, where each R groupis independently selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl, heterocyclic, substitutedheterocyclic, —SO₂-alkyl, —SO₂-substituted alkyl, —SO₂-alkenyl,—SO₂-substituted alkenyl, —SO₂-cycloalkyl, —SO₂-substituted cycloalkyl,—SO₂-aryl, —SO₂-substituted aryl, —SO₂-heteroaryl, —SO₂-substitutedheteroaryl, —SO₂-heterocyclic, —SO₂-substituted heterocyclic, providedthat both R groups are not hydrogen; or the R groups can be joinedtogether with the nitrogen atom to form a heterocyclic or substitutedheterocyclic ring.

[0112] “Aminoacyl” refers to the groups —NRC(O)alkyl, —NRC(O)substitutedalkyl, —NRC(O)cycloalkyl, —NRC(O)substituted cycloalkyl, —NRC(O)alkenyl,—NRC(O)substituted alkenyl, —NRC(O)alkynyl, —NRC(O)substituted alkynyl,—NRC(O)aryl, —NRC(O)substituted aryl, —NRC(O)heteroaryl,—NRC(O)substituted heteroaryl, —NRC(O)heterocyclic, and—NRC(O)substituted heterocyclic where R is hydrogen or alkyl and whereinalkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, subrtituted cycloalkyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic andsubstituted heterocyclic are as defined herein.

[0113] “Aminosulfonyl” refers to the groups —NRSO₂alkyl,—NRSO₂substituted alkyl, —NRSO₂cycloalkyl, —NRSO₂substituted cycloalkyl,—NRSO₂alkenyl, —NRSO₂substituted alkenyl, —NRSO₂alkynyl,—NRSO₂substituted alkynyl, —NRSO₂aryl, —NRSO₂substituted aryl,—NRSO₂heteroaryl, —NRSO₂substituted heteroaryl, —NRSO₂heterocyclic, and—NRSO₂substituted heterocyclic where R is hydrogen or alkyl and whereinalkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic andsubstituted heterocyclic are as defined herein.

[0114] “Aminocarbonyloxy” refers to the groups —NRC(O)O-alkyl,—NRC(O)O-substituted alkyl, —NRC(O)O-alkenyl, —NRC(O)O-substitutedalkenyl, —NRC(O)O-alkynyl, —NRC(O)O-substituted alkynyl,—NRC(O)O-cycloalkyl, —NRC(O)O-substituted cycloalkyl, —NRC(O)O-aryl,—NRC(O)O-substituted aryl, —NRC(O)O-heteroaryl, —NRC(O)O-substitutedheteroaryl, —NRC(O)O-heterocyclic, and —NRC(O)O-substituted heterocyclicwhere R is hydrogen or alkyl and wherein alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic and substituted heterocyclic are as definedherein.

[0115] “Aminosulfonyloxy” refers to the groups —NRSO₂O-alkyl,—NRSO₂O-substituted alkyl, —NRSO₂O-alkenyl, —NRSO₂O-substituted alkenyl,—NRSO₂O-alkynyl, —NRSO₂O-substituted alkynyl, —NRSO₂O-cycloalkyl,—NRSO₂O-substituted cycloalkyl, —NRSO₂O-aryl, —NRSO₂O-substituted aryl,—NRSO₂O-heteroaryl, —NRSO₂O-substituted heteroaryl,—NRSO₂O-heterocyclic, and —NRSO₂O-substituted heterocyclic where R ishydrogen or alkyl and wherein alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic and substituted heterocyclic are as definedherein.

[0116] “Oxycarbonylamino” refers to the groups —OC(O)NH₂, —OC(O)NRR,—OC(O)NR-alkyl, —OC(O)NR-substituted alkyl, —OC(O)NR-alkenyl,—OC(O)NR-substituted alkenyl, —OC(O)NR-alkynyl, —OC(O)NR-substitutedalkynyl, —OC(O)NR-cycloalkyl, —OC(O)NR-substituted cycloalkyl,—OC(O)NR-aryl, —OC(O)NR-substituted aryl, —OC(O)NR-heteroaryl,—OC(O)NR-substituted heteroaryl, —OC(O)NR-heterocyclic, and—OC(O)NR-substituted heterocyclic where R is hydrogen, alkyl or whereeach R is joined to form, together with the nitrogen atom a heterocyclicor substituted heterocyclic ring and wherein alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic and substituted heterocyclic are as definedherein.

[0117] “Oxythiocarbonylamino” refers to the groups —OC(S)NH₂, —OC(S)NRR,—OC(S)NR-alkyl, —OC(S)NR-substituted alkyl, —OC(S)NR-alkenyl,—OC(S)NR-substituted alkenyl, —OC(S)NR-alkynyl, —OC(S)NR-substitutedalkynyl, —OC(S)NR-cycloalkyl, —OC(S)NR-substituted cycloalkyl,—OC(S)NR-aryl, —OC(S)NR-substituted aryl, —OC(S)NR-heteroaryl,—OC(S)NR-substituted heteroaryl, —OC(S)NR-heterocyclic, and—OC(S)NR-substituted heterocyclic where R is hydrogen, alkyl or whereeach R is joined to form together with the nitrogen atom a heterocyclicor substituted heterocyclic ring and wherein alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic and substituted heterocyclic are as definedherein.

[0118] “Oxysulfonylamino” refers to the groups —OSO₂NH₂, —OSO₂NRR,—OSO₂NR-alkyl, —OSO₂NR-substituted alkyl, —OSO₂NR-alkenyl,—OSO₂NR-substituted alkenyl, —OSO₂NR-alkynyl, —OSO₂NR-substitutedalkynyl, —OSO₂NR-cycloalkyl, —OSO₂NR-substituted cycloalkyl,—OSO₂NR-aryl, —OSO₂NR-substituted aryl, —OSO₂NR-heteroaryl,—OSO₂NR-substituted heteroaryl, —OSO₂NR-heterocyclic, and—OSO₂NR-substituted heterocyclic where R is hydrogen, alkyl or whereeach R is joined to form, together with the nitrogen atom a heterocyclicor substituted heterocyclic ring and wherein alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic and substituted heterocyclic are as definedherein.

[0119] “Aminocarbonylamino” refers to the groups —NRC(O)NRR,—NRC(O)NR-alkyl, —NRC(O)NR-substituted alkyl, —NRC(O)NR-alkenyl,—NRC(O)NR-substituted alkenyl, —NRC(O)NR-alkynyl, —NRC(O)NR-substitutedalkynyl, —NRC(O)NR-aryl, —NRC(O)NR-substituted aryl,—NRC(O)NR-cycloalkyl, —NRC(O)NR-substituted cycloalkyl,—NRC(O)NR-heteroaryl, and —NRC(O)NR-substituted heteroaryl,—NRC(O)NR-heterocyclic, and —NRC(O)NR-substituted heterocyclic whereeach R is independently hydrogen, alkyl or where each R is joined toform together with the nitrogen atom a heterocyclic or substitutedheterocyclic ring as well as where one of the amino groups is blocked byconventional blocking groups such as Boc, Cbz, formyl, and the like andwherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic andsubstituted heterocyclic are as defined herein.

[0120] “Aminothiocarbonylamino” refers to the groups —NRC(S)NRR,—NRC(S)NR-alkyl, —NRC(S)NR-substituted alkyl, —NRC(S)NR-alkenyl,—NRC(S)NR-substituted alkenyl, —NRC(S)NR-alkynyl, —NRC(S)NR-substitutedalkynyl, —NRC(S)NR-aryl, —NRC(S)NR-substituted aryl,—NRC(S)NR-cycloalkyl, —NRC(S)NR-substituted cycloalkyl,—NRC(S)NR-heteroaryl, and —NRC(S)NR-substituted heteroaryl,—NRC(S)NR-heterocyclic, and —NRC(S)NR-substituted heterocyclic whereeach R is independently hydrogen, alkyl or where each R is joined toform together with the nitrogen atom a heterocyclic or substitutedheterocyclic ring as well as where one of the amino groups is blocked byconventional blocking groups such as Boc, Cbz, formyl, and the like andwherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic andsubstituted heterocyclic are as defined herein.

[0121] “Aminosulfonylamino” refers to the groups —NRSO₂NRR,—NRSO₂NR-alkyl, —NRSO₂NR-substituted alkyl, —NRSO₂NR-alkenyl,—NRSO₂NR-substituted alkenyl, —NRSO₂NR-alkynyl, —NRSO₂NR-substitutedalkynyl, —NRSO₂NR-aryl, —NRSO₂NR-substituted aryl, —NRSO₂NR-cycloalkyl,—NRSO₂NR-substituted cycloalkyl, —NRSO₂NR-heteroaryl, and—NRSO₂NR-substituted heteroaryl, —NRSO₂NR-heterocyclic, and—NRSO₂NR-substituted heterocyclic, where each R is independentlyhydrogen, alkyl or where each R is joined to form together with thenitrogen atom a heterocyclic or substituted heterocyclic ring as well aswhere one of the amino groups is blocked by conventional blocking groupssuch as Boc, Cbz, formyl, and the like and wherein alkyl, substitutedalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, heterocyclic and substituted heterocyclic are asdefined herein.

[0122] “Aryl” or “Ar” refers to an unsaturated aromatic carbocyclicgroup of from 6 to 14 carbon atoms having a single ring (e.g., phenyl)or multiple condensed rings (e.g., naphthyl or anthryl) which condensedrings may or may not be aromatic (e.g., 2-benzoxazolinone,2H-1,4-benzoxazin-3(4H)-one-7yl, and the like). Preferred aryls includephenyl and naphthyl.

[0123] Substituted aryl refers to aryl groups which are substituted withfrom 1 to 3 substituents selected from the group consisting of hydroxy,acyl, acylamino, thiocarbonylamino, acyloxy, alkyl, substituted alkyl,alkoxy, substituted alkoxy, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, amidino, alkylamidino, thioamidino, amino,aminoacyl, aminocarbonyloxy, aminocarbonylamino, aminothiocarbonylamino,aryl, substituted aryl, aryloxy, substituted aryloxy, cycloalkoxy,substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy,heterocyclyloxy, substituted heterocyclyloxy, carboxyl, carboxylalkyl,carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substitutedcycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl,carboxyl-substituted heteroaryl, carboxylheterocyclic,carboxyl-substituted heterocyclic, carboxylamido, cyano, thiol,thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl,thioheteroaryl, substituted thioheteroaryl, thiocycloalkyl, substitutedthiocycloalkyl, thioheterocyclic, substituted thioheterocyclic,cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, halo,nitro, heteroaryl, substituted heteroaryl, heterocyclic, substitutedheterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy,substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy,oxycarbonylamino, oxythiocarbonylamino, —S(O)₂-alkyl, —S(O)₂-substitutedalkyl, —S(O)₂-cycloalkyl, —S(O)₂-substituted cycloalkyl, —S(O)₂-alkenyl,—S(O)₂-substituted alkenyl, —S(O)₂-aryl, —S(O)₂-substituted aryl,—S(O)₂-heteroaryl, —S(O)₂-substituted heteroaryl, —S(O)₂-heterocyclic,—S(O)₂-substituted heterocyclic, —OS(O)₂-alkyl, —OS(O)₂-substitutedalkyl, —OS(O)₂-aryl, —OS(O)₂-substituted aryl, —OS(O)₂-heteroaryl,—OS(O)₂-substituted heteroaryl, —OS(O)₂-heterocyclic,—OS(O)₂-substituted heterocyclic, —OSO₂—NRR where R is hydrogen oralkyl, —NRS(O)₂-alkyl, —NRS(O)₂-substituted alkyl, —NRS(O)₂-aryl,—NRS(O)₂-substituted aryl, —NRS(O)₂-heteroaryl, —NRS(O)₂-substitutedheteroaryl, —NRS(O)₂-heterocyclic, —NRS(O)₂-substituted heterocyclic,—NRS(O)₂—NR-alkyl, —NRS(O)₂—NR-substituted alkyl, —NRS(O)₂—NR-aryl,—NRS(O)₂—NR-substituted aryl, —NRS(O)₂—NR-heteroaryl,—NRS(O)₂—NR-substituted heteroaryl, —NRS(O)₂—NR-heterocyclic,—NRS(O)₂—NR-substituted heterocyclic where R is hydrogen or alkyl, mono-and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- anddi-arylamino, mono- and di-substituted arylamino, mono- anddi-heteroarylamino, mono- and di-substituted heteroarylamino, mono- anddi-heterocyclic amino, mono- and di-substituted heterocyclic amino,unsymmetric di-substituted amines having different substituents selectedfrom alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, heterocyclic and substituted heterocyclic andamino groups on the substituted aryl blocked by conventional blockinggroups such as Boc, Cbz, formyl, and the like or substituted with—SO₂NRR where R is hydrogen or alkyl.

[0124] “Aryloxy” refers to the group aryl-O— which includes, by way ofexample, phenoxy, naphthoxy, and the like.

[0125] “Substituted aryloxy” refers to substituted aryl-O— groups.

[0126] “Aryloxyaryl” refers to the group -aryl-O-aryl.

[0127] “Substituted aryloxyaryl” refers to aryloxyaryl groupssubstituted with from 1 to 3 substituents on either or both aryl ringsselected from the group consisting of hydroxy, acyl, acylamino,thiocarbonylamino, acyloxy, alkyl, substituted alkyl, alkoxy,substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, amidino, alkylamidino, thioamidino, amino, aminoacyl,aminocarbonyloxy, aminocarbonylamino, aminothiocarbonylamino, aryl,substituted aryl, aryloxy, substituted aryloxy, cycloalkoxy, substitutedcycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy,substituted heterocyclyloxy, carboxyl, carboxylalkyl,carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substitutedcycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl,carboxyl-substituted heteroaryl, carboxylheterocyclic,carboxyl-substituted heterocyclic, carboxylamido, cyano, thiol,thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl,thioheteroaryl, substituted thioheteroaryl, thiocycloalkyl, substitutedthiocycloalkyl, thioheterocyclic, substituted thioheterocyclic,cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, halo,nitro, heteroaryl, substituted heteroaryl, heterocyclic, substitutedheterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy,substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy,oxycarbonylamino, oxythiocarbonylamino, —S(O)₂-alkyl, —S(O)₂-substitutedalkyl, —S(O)₂-cycloalkyl, —S(O)₂-substituted cycloalkyl, —S(O)₂-alkenyl,—S(O)₂-substituted alkenyl, —S(O)₂-aryl, —S(O)₂-substituted aryl,—S(O)₂-heteroaryl, —S(O)₂-substituted heteroaryl, —S(O)₂-heterocyclic,—S(O)₂-substituted heterocyclic, —OS(O)₂-alkyl, —OS(O)₂-substitutedalkyl, —OS(O)₂-aryl, —OS(O)₂-substituted aryl, —OS(O)₂-heteroaryl,—OS(O)₂-substituted heteroaryl, —OS(O)₂-heterocyclic,—OS(O)₂-substituted heterocyclic, —OSO₂—NRR where R is hydrogen oralkyl, —NRS(O)₂-alkyl, —NRS(O)₂-substituted alkyl, —NRS(O)₂-aryl,—NRS(O)₂-substituted aryl, —NRS(O)₂-heteroaryl, —NRS(O)₂-substitutedheteroaryl, —NRS(O)₂-heterocyclic, —NRS(O)₂-substituted heterocyclic,—NRS(O)₂—NR-alkyl, —NRS(O)₂—NR-substituted alkyl, —NRS(O)₂—NR-aryl,—NRS(O)₂—NR-substituted aryl, —NRS(O)₂—NR-heteroaryl,—NRS(O)₂—NR-substituted heteroaryl, —NRS(O)₂—NR-heterocyclic,—NRS(O)₂—NR-substituted heterocyclic where R is hydrogen or alkyl, mono-and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- anddi-arylamino, mono- and di-substituted arylamino, mono- anddi-heteroarylamino, mono- and di-substituted heteroarylamino, mono- anddi-heterocyclic amino, mono- and di-substituted heterocyclic amino,unsymmetric di-substituted amines having different substituents selectedfrom alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, heterocyclic and substituted heterocyclic andamino groups on the substituted aryl blocked by conventional blockinggroups such as Boc, Cbz, formyl, and the like or substituted with—SO₂NRR where R is hydrogen or alkyl.

[0128] “Cycloalkyl” refers to cyclic alkyl groups of from 3 to 8 carbonatoms having a single cyclic ring including, by way of example,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl and thelike. Excluded from this definition are multi-ring alkyl groups such asadamantanyl, etc.

[0129] “Cycloalkenyl” refers to cyclic alkenyl groups of from 3 to 8carbon atoms having single or multiple unsaturation but which are notaromatic.

[0130] “Substituted cycloalkyl” and “substituted cycloalkenyl” refer toa cycloalkyl and cycloalkenyl groups, preferably of from 3 to 8 carbonatoms, having from 1 to 5 substituents selected from the groupconsisting of oxo (═O), thioxo (═S), alkoxy, substituted alkoxy, acyl,acylamino, thiocarbonylamino, acyloxy, amino, amidino, alkylamidino,thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino,aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy,aryloxyaryl, substituted aryloxyaryl, halogen, hydroxyl, cyano, nitro,carboxyl, carboxylalkyl, carboxyl-substituted alkyl,carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl,carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substitutedheteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic,cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol,thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl,thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substitutedthioheteroaryl, thioheterocyclic, substituted thioheterocyclic,heteroaryl, substituted heteroaryl, heterocyclic, substitutedheterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy,substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy,oxycarbonylamino, oxythiocarbonylamino, —OS(O)₂-alkyl,—OS(O)₂-substituted alkyl, —OS(O)₂-aryl, —OS(O)₂-substituted aryl,—OS(O)₂-heteroaryl, —OS(O)₂-substituted heteroaryl,—OS(O)₂-heterocyclic, —OS(O)₂-substituted heterocyclic, —OSO₂—NRR whereR is hydrogen or alkyl, —NRS(O)₂-alkyl, —NRS(O)₂-substituted alkyl,—NRS(O)₂-aryl, —NRS(O)₂-substituted aryl, —NRS(O)₂-heteroaryl,—NRS(O)₂-substituted heteroaryl, —NRS(O)₂-heterocyclic,—NRS(O)₂-substituted heterocyclic, —NRS(O)₂—NR-alkyl,—NRS(O)₂—NR-substituted alkyl, —NRS(O)₂—NR-aryl, —NRS(O)₂—NR-substitutedaryl, —NRS(O)₂—NR-heteroaryl, —NRS(O)₂—NR-substituted heteroaryl,—NRS(O)₂—NR-heterocyclic, —NRS(O)₂—NR-substituted heterocyclic where Ris hydrogen or alkyl, mono- and di-alkylamino, mono- and di-(substitutedalkyl)amino, mono- and di-arylamino, mono- and di-substituted arylamino,mono- and di-heteroarylamino, mono- and di-substituted heteroarylamino,mono- and di-heterocyclic amino, mono- and di-substituted heterocyclicamino, unsymmetric di-substituted amines having different substituentsselected from alkyl, substituted alkyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl, heterocyclic and substitutedheterocyclic and substituted alkynyl groups having amino groups blockedby conventional blocking groups such as Boc, Cbz, formyl, and the likeor alkynyl/substituted alkynyl groups substituted with —SO₂-alkyl,—SO₂-substituted alkyl, —SO₂-alkenyl, —SO₂-substituted alkenyl,—SO₂-cycloalkyl, —SO₂-substituted cycloalkyl, —SO₂-aryl,—SO₂-substituted aryl, —SO₂-heteroaryl, —SO₂-substituted heteroaryl,—SO₂-heterocyclic, —SO₂-substituted heterocyclic and —SO₂NRR where R ishydrogen or alkyl.

[0131] “Cycloalkoxy” refers to —O-cycloalkyl groups.

[0132] “Substituted cycloalkoxy” refers to —O-substituted cycloalkylgroups.

[0133] “Cycloalkenoxy” refers to —O-cycloalkenyl groups.

[0134] “Substituted cycloalkenoxy” refers to —O-substituted cycloalkenylgroups.

[0135] “Guanidino” refers to the groups-NRC(═NR)NRR, —NRC(═NR)NR-alkyl,—NRC(═NR)NR-substituted alkyl, —NRC(═NR)NR-alkenyl,—NRC(═NR)NR-substituted alkenyl, —NRC(═NR)NR-alkynyl,—NRC(═NR)NR-substituted alkynyl, —NRC(═NR)NR-aryl,—NRC(═NR)NR-substituted aryl, —NRC(═NR)NR-cycloalkyl,—NRC(═NR)NR-heteroaryl, —NRC(═NR)NR-substituted heteroaryl,—NRC(═NR)NR-heterocyclic, and —NRC(═NR)NR-substituted heterocyclic whereeach R is independently hydrogen and alkyl as well as where one of theamino groups is blocked by conventional blocking groups such as Boc,Cbz, formyl, and the like and wherein alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic and substituted heterocyclic are as definedherein.

[0136] “Guanidinosulfone” refers to the groups —NRC(═NR)NRSO₂-alkyl,—NRC(═NR)NRSO₂-substituted alkyl, —NRC(═NR)NRSO₂-alkenyl,—NRC(═NR)NRSO₂-substituted alkenyl, —NRC(═NR)NRSO₂-alkynyl,—NRC(═NR)NRSO₂-substituted alkynyl, —NRC(═NR)NRSO₂-aryl,—NRC(═NR)NRSO₂-substituted aryl, —NRC(═NR)NRSO₂-cycloalkyl,—NRC(═NR)NRSO₂-substituted cycloalkyl, —NRC(═NR)NRSO₂-heteroaryl, and—NRC(═NR)NRSO₂-substituted heteroaryl, —NRC(═NR)NRSO₂-heterocyclic, and—NRC(═NR)NRSO₂-substituted heterocyclic where each R is independentlyhydrogen and alkyl and wherein alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic and substituted heterocyclic are as definedherein.

[0137] “Halo” or “halogen” refers to fluoro, chloro, bromo and iodo andpreferably is either chloro or bromo.

[0138] “Heteroaryl” refers to an aromatic carbocyclic group of from 2 to10 carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogenand sulfur within the ring or oxides thereof. Such heteroaryl groups canhave a single ring (e.g., pyridyl or furyl) or multiple condensed rings(e.g., indolizinyl or benzothienyl). Additionally, the heteroatoms ofthe heteroaryl group may be oxidized, i.e., to form pyridine N-oxides or1,1-dioxo-1,2,5-thiadiazoles and the like. Preferred heteroaryls includepyridyl, pyrrolyl, indolyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl,1-oxo-1,2,5-thiadiazolyl and 1,1-dioxo-1,2,5-thiadiazolyl. The term“heteroaryl having two nitrogen atoms in the heteroaryl ring” refers toa heteroaryl group having two, and only two, nitrogen atoms in theheteroaryl ring and optionally containing 1 or 2 other heteroatoms inthe heteroaryl ring, such as oxygen or sulfur

[0139] “Substituted heteroaryl” refers to heteroaryl groups which aresubstituted with from 1 to 3 substituents selected from the groupconsisting of hydroxy, acyl, acylamino, thiocarbonylamino, acyloxy,alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, amidino,alkylamidino, thioamidino, amino, aminoacyl, aminocarbonyloxy,aminocarbonylamino, aminothiocarbonylamino, aryl, substituted aryl,aryloxy, substituted aryloxy, cycloalkoxy, substituted cycloalkoxy,heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substitutedheterocyclyloxy, carboxyl, carboxylalkyl, carboxyl-substituted alkyl,carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl,carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substitutedheteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic,carboxylamido, cyano, thiol, thioalkyl, substituted thioalkyl, thioaryl,substituted thioaryl, thioheteroaryl, substituted thioheteroaryl,thiocycloalkyl, substituted thiocycloalkyl, thioheterocyclic,substituted thioheterocyclic, cycloalkyl, substituted cycloalkyl,guanidino, guanidinosulfone, halo, nitro, heteroaryl, substitutedheteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy,substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy,heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino,oxythiocarbonylamino, —S(O)₂-alkyl, —S(O)₂-substituted alkyl,—S(O)₂-cycloalkyl, —S(O)₂-substituted cycloalkyl, —S(O)₂-alkenyl,—S(O)₂-substituted alkenyl, —S(O)₂-aryl, —S(O)₂-substituted aryl,—S(O)₂-heteroaryl, —S(O)₂-substituted heteroaryl, —S(O)₂-heterocyclic,—S(O)₂-substituted heterocyclic, —OS(O)₂-alkyl, —OS(O)₂-substitutedalkyl, —OS(O)₂-aryl, —OS(O)₂-substituted aryl, —OS(O)₂-heteroaryl,—OS(O)₂-substituted heteroaryl, —OS(O)₂-heterocyclic,—OS(O)₂-substituted heterocyclic, —OSO₂—NRR where R is hydrogen oralkyl, —NRS(O)-alkyl, —NRS(O)₂-substituted alkyl, —NRS(O)₂-aryl,—NRS(O)₂-substituted aryl, —NRS(O)₂-heteroaryl, —NRS(O)₂-substitutedheteroaryl, —NRS(O)₂-heterocyclic, —NRS(O)₂-substituted heterocyclic,—NRS(O)₂—NR-alkyl, —NRS(O)₂—NR-substituted alkyl, —NRS(O)₂—NR-aryl,—NRS(O)₂—NR-substituted aryl, —NRS(O)₂—NR-heteroaryl,—NRS(O)₂—NR-substituted heteroaryl, —NRS(O)₂—NR-heterocyclic,—NRS(O)₂—NR-substituted-heterocyclic where R is hydrogen or alkyl, mono-and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- anddi-arylamino, mono- and di-substituted arylamino, mono- anddi-heteroarylamino, mono- and di-substituted heteroarylamino, mono- anddi-heterocyclic amino, mono- and di-substituted heterocyclic amino,unsymmetric di-substituted amines having different substituents selectedfrom alkyl, substituted alky, aryl, substituted aryl, heteroaryl,substituted heteroaryl, heterocyclic and substituted heterocyclic andamino groups on the substituted aryl blocked by conventional blockinggroups such as Boc, Cbz, formyl, and the like or substituted with—SO₂NRR where R is hydrogen or alkyl.

[0140] “Heteroaryloxy” refers to the group —O-heteroaryl and“substituted heteroaryloxy” refers to the group —O-substitutedheteroaryl.

[0141] “Heterocycle” or “heterocyclic” refers to a saturated orunsaturated group having a single ring or multiple condensed rings, from1 to 10 carbon atoms and from 1 to 4 hetero atoms selected fromnitrogen, sulfur or oxygen within the ring wherein, in fused ringsystems, one or more of the rings can be aryl or heteroaryl.

[0142] “Substituted heterocyclic” refers to heterocycle groups which aresubstituted with from 1 to 3 substituents selected from the groupconsisting of oxo (═O), thioxo (═S), alkoxy, substituted alkoxy, acyl,acylamino, thiocarbonylamino, acyloxy, amino, amidino, alkylamidino,thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino,aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy,aryloxyaryl, substituted aryloxyaryl, halogen, hydroxyl, cyano, nitro,carboxyl, carboxylalkyl, carboxyl-substituted alkyl,carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl,carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substitutedheteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic,cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol,thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl,thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substitutedthioheteroaryl, thioheterocyclic, substituted thioheterocyclic,heteroaryl, substituted heteroaryl, heterocyclic, substitutedheterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy,substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy,oxycarbonylamino, oxythiocarbonylamino, —OS(O)₂-alkyl,—OS(O)₂-substituted alkyl, —OS(O)₂-aryl, —OS(O)₂-substituted aryl,—OS(O)₂-heteroaryl, —OS(O)₂-substituted heteroaryl,—OS(O)₂-heterocyclic, —OS(O)₂-substituted heterocyclic, —OSO₂—NRR whereR is hydrogen or alkyl, —NRS(O)₂-alkyl, —NRS(O)₂-substituted alkyl,—NRS(O)₂-aryl, —NRS(O)₂-substituted aryl, —NRS(O)₂-heteroaryl,—NRS(O)₂-substituted heteroaryl, —NRS(O)₂-heterocyclic,—NRS(O)₂-substituted heterocyclic, —NRS(O)₂—NR-alkyl,—NRS(O)₂—NR-substituted alkyl, —NRS(O)₂—NR-aryl, —NRS(O)₂—NR-substitutedaryl, —NRS(O)₂—NR-heteroaryl, —NRS(O)₂—NR-substituted heteroaryl,—NRS(O)₂—NR-heterocyclic, —NRS(O)₂—NR-substituted heterocyclic where Ris hydrogen or alkyl, mono- and di-alkylamino, mono- and di-(substitutedalkyl)amino, mono- and di-arylamino, mono- and di-substituted arylamino,mono- and di-heteroarylamino, mono- and di-substituted heteroarylamino,mono- and di-heterocyclic amino, mono- and di-substituted heterocyclicamino, unsymmetric di-substituted amines having different substituentsselected from alkyl, substituted alkyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl, heterocyclic and substitutedheterocyclic and substituted alkynyl groups having amino groups blockedby conventional blocking groups such as Boc, Cbz, formyl, and the likeor alkynyl/substituted alkynyl groups substituted with —SO₂-alkyl,—SO₂-substituted alkyl, —SO₂-alkenyl, —SO₂-substituted alkenyl,—SO₂-cycloalkyl, —SO₂-substituted cycloalkyl, —SO₂-aryl,—SO₂-substituted aryl, —SO₂-heteroaryl, —SO₂-substituted heteroaryl,—SO₂-heterocyclic, —SO₂-substituted heterocyclic and —SO₂NRR where R ishydrogen or alkyl.

[0143] Examples of heterocycles and heteroaryls include, but are notlimited to, azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine,pyrimidine, pyridazine, indolizine, isoindole, indole, dihydroindole,indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine,naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine,carbazole, carboline, phenanthridine, acridine, phenanthroline,isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine,imidazolidine, imidazoline, piperidine, piperazine, indoline,phthalimide, 1,2,3,4-tetrahydroisoquinoline,4,5,6,7-tetrahydrobenzo[b]thiophene, thiazole, thiazolidine, thiophene,benzo[b]thiophene, morpholino, thiomorpholino, piperidinyl, pyrrolidine,tetrahydrofuranyl, and the like.

[0144] “Heterocyclyloxy” refers to the group —O-heterocyclic and“substituted heterocyclyloxy” refers to the group —O-substitutedheterocyclic.

[0145] “Thiol” refers to the group —SH.

[0146] “Thioalkyl” refers to the groups —S-alkyl

[0147] “Substituted thioalkyl” refers to the group —S-substituted alkyl.

[0148] “Thiocycloalkyl” refers to the groups —S-cycloalkyl.

[0149] “Substituted thiocycloalkyl” refers to the group —S-substitutedcycloalkyl.

[0150] “Thioaryl” refers to the group —S-aryl and “substituted thioaryl”refers to the group —S-substituted aryl.

[0151] “Thioheteroaryl” refers to the group —S-heteroaryl and“substituted thioheteroaryl” refers to the group —S-substitutedheteroaryl.

[0152] “Thioheterocyclic” refers to the group —S-heterocyclic and“substituted thioheterocyclic” refers to the group —S-substitutedheterocyclic.

[0153] “Pharmaceutically acceptable salt” refers to pharmaceuticallyacceptable salts of a compound of Formula I which salts are derived froma variety of organic and inorganic counter ions well known in the artand include, by way of example only, sodium, potassium, calcium,magnesium, ammonium, tetraalkylammonium, and the like; and when themolecule contains a basic functionality, salts of organic or inorganicacids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate,maleate, oxalate and the like.

Methodology

[0154] The compounds of the invention may be prepared by a number ofprocesses as generally described below and more specifically in theExamples hereinafter. In the following process description, the symbolsR-R⁶ (including R^(a)), Ar, Alk², m and r, when used in the formulaedepicted are to be understood to represent those groups described abovein relation to formula (1) and formula (2) unless otherwise indicated.In the reactions described below, it may be necessary to protectreactive functional groups, for example hydroxy, amino, thio or carboxygroups, where these are desired in the final product, to avoid theirunwanted participation in the reactions. Conventional protecting groupsmay be used in accordance with standard practice [see, for example,Green, T. W. in “Protective Groups in Organic Synthesis”, John Wiley andSons, 1991]. In some instances, deprotection may be the final step inthe synthesis of a compound of formula (1) and the processes accordingto the invention described hereinafter are to be understood to extend tosuch removal of protecting groups. For convenience the processesdescribed below all refer to a preparation of a compound of formula (1)but clearly the description applies equally to the preparation ofcompounds of formula (2).

[0155] Thus according to a further aspect of the invention, a compoundof formula (1) in which R is a —CO₂H group may be obtained by hydrolysisof an ester of formula (3):

[0156] where R^(b) is an alkyl group, for example a C₁₋₆alkyl group asdescribed above.

[0157] The hydrolysis may be performed using either an acid or a basedepending on the nature of R^(b), for example an organic acid such astrifluoroacetic acid or an inorganic base such as lithium or potassiumhydroxide optionally in an aqueous organic solvent such as an amide,e.g., a substituted amide such as dimethylformamide, an ether, e.g. acyclic ether such as tetrahydrofuran or dioxane or an alcohol, e.g.methanol at around ambient temperature. Where desired, mixtures of suchsolvents may be used.

[0158] Esters of formula (3) may be prepared by coupling an amine offormula (4):

[0159] or a salt thereof with a reagent Ar—X¹ where X¹ is a leavinggroup. Particular leaving groups represented by X¹ include for examplehalogen atoms such as fluorine, chlorine or bromine atoms orsulphonyloxy groups such as a methylsulphonyloxy group.

[0160] The coupling reaction may be performed using standard conditionsfor reactions of this type. Thus for example the reaction may be carriedout in a solvent, for example an alcohol, e.g. methanol or ethanol, at atemperature from around ambient to the reflux temperature, optionally inthe presence of a base, e.g. an organic base such as an amine, e.g.triethylamine or N,N-diisopropylethylamine, or a cyclic amine, such asN-methylmorpholine or pyridine.

[0161] Where desired, compounds of formula (4) may be linked to asuitable solid support, for example via their carboxylate group (R^(b)is H), and subsequently converted to compounds of formula (1) linked tothe solid support via the methods just described. Displacement from theresin by any convenient method for example by cleavage using an acidsuch as trifluoroacetic acid, then gives the desired compound of formula(1). Particular examples of such solid-phase syntheses are given in theExamples herein.

[0162] The amines of formula (4) may be obtained from simpler, knowncompounds by one or more standard synthetic methods employing C—C bondformation substitution, 1,4-addition, oxidation, reduction or cleavagereactions. Particular C—C bond forming reactions include theHornerEmmons and Wittig reactions. Particular substitution approachesinclude conventional alkylation, arylation, heteroarylation, acylation,thioacylation, halogenation, sulphonylation, nitration, formylation andcoupling procedures. It will be appreciated that these methods may alsobe used to obtain or modify other compounds of formulae (1) and (2)where appropriate functional groups exist in these compounds.Additionally, although a number of the intermediates ArX¹ for use in thecoupling reaction described above are known, others can be derivedtherefrom using these standard synthetic methods.

[0163] Thus compounds of the invention and intermediates thereto may beprepared by alkylation, arylation or heteroarylation. For example,compounds of formula II can be prepared from the phenolic intermediateby reaction with, for example, 4-nitrophenyl chloroformate followed byreaction with an amine of the formula

R¹R²NH

[0164] where R¹ and R² are as defined above. Further examples of thisreaction are set forth in U.S. patent application Ser. No. 09/489,377and WO 00/18759 both of which are incorporated herein by reference inits entirety.

[0165] Salts of compounds of formula (1) and (2) may be prepared byreaction of a compound of formula (1) or (2) with an appropriate base ina suitable solvent or mixture of solvents e.g. an organic solvent suchas an ether e.g. diethylether, or an alcohol, e.g. ethanol usingconventional procedures.

[0166] Where it is desired to obtain a particular enantiomer of acompound of formula (1) this may be produced from a correspondingmixture of enantiomers using any suitable conventional procedure forresolving enantiomers.

[0167] Thus for example diastereomeric derivatives, e.g. salts, may beproduced by reaction of a mixture of enantiomers of formula (1) e.g. aracemate, and an appropriate chiral compound, e.g. a chiral base. Thediastereomers may then be separated by any convenient means, for exampleby crystallization and the desired enantiomer recovered, e.g. bytreatment with an acid in the instance where the diastereomer is a salt.In another resolution process a racemate of formula (1) may be separatedusing chiral High Performance Liquid Chromatography. Alternatively, ifdesired a particular enantiomer may be obtained by using an appropriatechiral intermediate in one of the processes described above.

[0168] Chromatography, recrystalliation and other conventionalseparation procedures may also be used with intermediates or finalproducts where it is desired to obtain a particular geometric isomer ofthe invention.

[0169] The following Examples illustrate the invention. Examples 1-168illustrate reaction schemes for use in preparing prior art compounds andExample 169 shows how such reaction schemes could be used to preparecompounds of this invention. All temperatures are in ° C. The followingabbreviations are used:

[0170] NMM—N-methylmorpholine; EtOAc—ethyl acetate;

[0171] MeOH—methanol; BOC—butoxycarbonyl;

[0172] DCM—dichloromethane; AcOH—acetic acid;

[0173] DIPEA—N,N-diisopropylethylamine; DMF—dimethylformamide;

[0174] LIDA—lithium N,N-diisopropylamide;

[0175] mCPBA—3-chloroperoxybenzoic acid

[0176] All NMR's were obtained at 300 mHz.

[0177] Intermediate 1

[0178] 3,5-Dichloropyridine-4-carboxylic Acid

[0179] A solution of 3,5-dichloropyridine (5.00 g, 33.8 mmol) in THF (25ml) was added to a solution of LDA [generated from nBuLi (2.5M solutionhexanes, 14.9 ml, 37.2 mmol) and diisopropylamine (4.108, 5.7 ml, 40.6mmol)] in THF (25 ml) at −78° then CO₂ gas was bubbled through to give aclear brown solution that slowly gave a precipitate, warmed to roomtemperature over 2 h, then quenched with water (20 ml) and partitionedbetween diethylether (100 ml) and 1 M NaOH (100 ml). The aqueous layerwas separated and acidified to pH1 with concentrated hydrochloric acidand then extracted with 10% MeOH in DCM (100 ml×3). The combined organiclayers were dried (MgSO4) and the solvent removed in vacuo to give abrown solid that was recrystallised from ethanol and dried under vacuumto give the title compound as pinkish crystals (2.638, 41%): δH (DMSOd₆) 8.72 (2H, s).

[0180] Intermediate 2

[0181](S)-Ethyl-3-[4-(3,5-dichloropyrid-4-ylcarboxamido)phenyl]-2-(t-butoxycarbonylamino)propionate

[0182] A slurry of Intermediate 1 (51.2 g, D.267 mol) in DCM (195 ml)and thionyl chloride (195 ml, 2.67 mol) was treated with DMF (5 drops)and heated to reflux for 4 h. The reaction was concentrated in vacuo andazeotroped with toluene (2×50 ml) to give the acid chloride derivativeof intermediate 1 as a yellow solid which was used without furtherpurification. A solution of(S)-ethyl-3-(4-aminophenyl)-2-(t-butoxycarbonylamino)propionate (130.8g, 0.425 mol) in DCM (800 ml) was cooled to 0° and treated with NMM(56.0 ml, 0.51 mol), stirred 5 minutes and then a solution of the acidchloride (98.3 g, 0.468 mol) in DCM (200 ml) was added dropwise keepingthe reaction temperature below 5°. The reaction was stirred for 1 h,quenched with NaHC₃ solution (500 ml), the organic layer separated,washed with NaHCO₃ solution (500 ml), 10% citric acid solution (500 ml)and NaHCO₃ solution (500 ml), dried (MgSO₄) and concentrated in vacuo togive a yellow solid which was recrystallised (EtOAc/Hexane) to give thetile compound (140 g, 69%): δH (DMSO d₆) 8.80 (2H, s), 7.55 (2H, d, J8.5 Hz), 7.23 (2H, d, J 8.5 Hz), 4.00 (3H, m), 3.40 (2H, br. s), 2.90(1H, m), 2.80 (1H, m), 1.30 (9H, s), 1.25 (3H, t); m/z (EI⁺, 70V) 504.

[0183] Intermediate 3

[0184](S)-Ethyl-3-[4-(3,5-dichloropyrid-4-ylcarboxamido)phenyl]-2-aminopropionatehydrochloride

[0185] A solution of Intermediate 2 (70.0 g, 0.146 mol) in EtOAc (500ml) and 1,4dioxan (50 ml) was treated with a solution of HCl in EtOAc(500 ml, 3M), and stirred at room temperature for 4 h. The reaction wasconcentrated in vacuo to give a yellow soild which was triturated withEt₂O then recrystallised (EtOAc/hexane) to give the title compound (59.3g, 92%): δH (DMSO d₆) 11.10 (1H, s), 8.70 (2H, s), 7.55 (2H, d, J 8.4Hz), 7.25 (2H, d, J 8.4 Hz), 4.10 (3H, m), 3.10 (2H, m), 1.10 (3H, m);m/z (EI⁺, 70V) 382.

[0186] Intermediate 4

[0187](S)-Methyl-3-[4-(3,5-dichloropyrid-4-ylcarboxamido)phenyl]-2-aminopropionateHydrochloride

[0188] The title compound was prepared in a similar manner toIntermediate 3 starting from(S)-methyl-3-(4-aminophenyl)-2-(t-butoxycarbonylamino) propionate andIntermediate 1:δH (DMSO d₆) 11.08 (1H, s), 8.77 (2H, s), 8.73 (3H, br.m), 7.63 (2H, d, J 8.5 Hz), 7.25 (2H, d, J 8.5 Hz), 4.24 (1H, m), 3.70(3H, s), 3.16 (2H, m); m/z (EI⁺, 70V) 368 and 370.

[0189] Intermediate 5

[0190] 3,5-Dichloro-4-hydroxymethylpyridine

[0191] A solution of 3,5-dichloropyridine-4-carboxaldehyde (1.34 g, 7.6mmol) in MeOH (10 ml) was treated with NaBH₄ (0.29 g, 7.6 mmol) andstirred at room temperature for 2 h. The reaction was quenched withwater (5 ml) and concentrated in vacuo. The residue was partitionedbetween EtOAc (20 ml) and 10% HCl (10 ml). The aqueous layer wasextracted with EtOAc and the combined organic extracts washed with 10%NaHCO₃ solution, dried (MgSO₄) and concentrated in vacuo to give thetitle compound as a white solid (1.05 g, 78%): δH (CDCl₃) 8.52 (2H, s),4.94 (2H, br. s), 2.28 (1H, br. s).

[0192] Intermediate 6

[0193] 3,5-Dichloro-4-bromomethylpyridine

[0194] A solution of Intermediate 5 (0.50 g, 2.80 mmol) in DCM (10 ml)was treated with thionyl bromide (3.51 g, 1.32 ml, 16.9 mmol) and heatedto reflux for 3 h. The reaction was quenched with 10% NaHCO₃ solution(10 ml) and extracted with DCM (25 ml). The organic layer was dried(MgSO₄) and concentrated in vacuo to give the title compound as a yellowoil that solidified on standing (0.65 g, 96%) and was used withoutfurther purification: δH (CDCl₃) 8.50 (2H, s), 4.63 (2H, s); m/z (EI⁺,60V) 242.

[0195] Intermediate 7

[0196] (S)-Ethyl (O-(3,5-dichloropyrid-4-yl)methyl]-L-tyrosineHydrochloride

[0197] The title compound was obtained by reaction of N-Boc-L-tyrosineethyl ester with Intermediate 6 in the presence of sodium hydride,followed by Boc deprotection, using methods well known to a personskilled in the art: δH (DMSO d₆) 8.79-8.60 (3H, m), 7.20 (2H, d, J 8.6Hz), 7.00 (2H, d, J 8.6 MHz), 5.21 (2H, s), 4:34-4.20 (1H, m), 3.67 (3H,s); m/z (EI⁺, 70V) 355 and 357.

[0198] Intermediate 8

[0199] S-Ethyl3-(4-nitrophenyl)-2-(6-chloropyrimidin-4-ylamino)propionate

[0200] A solution of 4-nitro-L-phenylalanine ethyl ester (3.22 g, 13.53mmol), DIPEA (2.35 ml, 1.75 g, 13.56 mmol) and 4,6-dichloropyrimidine(2.02 g, 13.55 mmol) in absolute ethanol (16 ml) was stirred at 70° for18 h under N. The volatiles were removed in vacuo and the residuepartitioned between EtOAc (70 ml) and water (40 ml). The phases wereseparated and the aqueous phase re-extracted with EtOAc (2×30 ml). Thecombined organic extracts were washed with brine (10 ml), dried (Na₂SO₄)and evaporated in vacuo to afford a dark oil. Chromatography (silica, 2%MeOH/DCM) afforded the title compound as an orange oil which slowlysolidified (4.03 g, 85%); δH (CDCl₃) 8.39 (1H, s), 8.13 (2H, d, J 8.7Hz), 7.28 (2H, d, J 8.7 Hz), 6.43 (1H, s), 5.55 (1H, br d, J 7.0 Hz),5.10-5.00 (1H, br m), 4.21(2H, q, J 7.1 Hz), 3.27 (1H, dd, J 13.8, 6.0Hz), 3.27 (1H, dd, J 13.8, 5.7 Hz) and 1.26 (3H, t, J 7.1 Hz); m/z (EI⁺,100V) 351.

[0201] Intermediate 9

[0202] S-Ethyl3-(4-aminophenyl)-2(6-chloropyrimidin-4-ylamino)propionate

[0203] A mixture of Intermediate 8 (1 g, 2.85 mmol) and 10% palladium onactivated carbon (100 mg) in absolute ethanol (40 ml) was stirred undera hydrogen atmosphere (balloon) at room temperature for 1.5 h. Afterdegassing and N₂ flushing, the catalyst was removed by filtrationthrough a Celite® pad and washed with DCM. The filtrate was evaporatedin vacuo and the obtained yellow oil subjected to chromatorgaphy(silica: 3% MeOH/DCM). The title compound was isolated as a yellow oil(0.42 g, 46%) δH (CDCl₃) 8.33 (1H, s), 6.86 (2H, d, J 8.4 Hz), 6.56 (2H,d, J 8.4 Hz), 6.30 (1H, s), 5.27 (1H, br s), 4.84 (1H, br s), 4.19 (2H,q, J 7.1 Hz), 3.64 (2H, br s), 3.10 (1H, dd, J 14.0, 5.6 Hz), 3.01 (1H,dd, J 14.0, 6.1 Hz) and 1.26 (3H, t, J 7.1 Hz); m/z (EI⁺, 100V) 321.

[0204] Intermediate 10

[0205] S-Ethyl3-[4-(3,5-dichloropyrid-4-ylcarboxamido)-phenyl]-2-(4-methoxy-6-chloro-1,3,5-triazin-2-ylaminoPropionate

[0206] Intermediate 3 (0.5 g, 1.19 mmol) in dry acetonitrile (5 ml)under nitrogen was added to 2,4 dichloro-6-methoxy-1,3,5-triazine (0.26g, 1.43 mmol). The mixture was cooled to −30° and DIPEA (0.46 ml) wasadded slowly over 10 min. The reaction was allowed to warm to 5° over 2h and then ethyl acetate and aqueous sodium bicarbonate were added andthe mixture shaken and separated. The organic layer was washed withwater, dried (MgSO₄) and the solvent removed in vacuo. The product waspurified by flash chromatography (silica; EtOAC/Hexane 1:1) to affordthe title compound as a white solid (0.53 g, 85%): δH (DMSO d₆) 10.55(1H, s), 8.70 (2H, s), 8.51-8.40 (1H,m), 7.50 (2H, d, J 8.4 Hz), 7.29(2H, d, J 84 Hz), 4.60 (1H, m), 4.12 (2H, d, J 8.4 Hz), 3.87 (3H, s),3.23-3.15 (2H, m), 1.16 (3H, t, J 7.2 Hz); m/z (EI⁺, 70V) 527.

[0207] Intermediate 11

[0208] S-Ethyl3-(4-hydraxyphenyl)-2-[(4,6-dimethoxy-1,3,5-triazin-2-yl)amino]propionate

[0209] A mixture of L-tyrosine ethyl ester hydrochloride (0.50 g, 2.0mmol) and DIPEA (0.74 ml, 4.4 mmol) in CH₃CN (8 ml) was stirred at roomtemperature for 15 minutes and then2-chloro-4,6-dimethoxy-1,3,5-triazine (0.43 g, 2.2 mmol) was added, andthe reaction stirred overnight then concentrated in vacuo. The residuewas partitioned between EtOAc (50 ml) and NaHCO₃ solution (50 ml). Theorganic layer was washed with 10% citric acid solution (50 ml), NaHCO₃solution (50 ml) and water (50 ml), dried (MgSO₄) and concentrated invacuo to give the title compound as a colourless gum (0.48 g, 68%): δH(DMSO d₆) 6.90 (2H, d), 6.65 (2H, d), 5.90 (1H, m), 4.90 (1H, m), 4.10(2H, m), 3.95 (3H, s), 3.90 (3H, s), 3.10 (2H, m), 1.20 (3H, t, J 7.1Hz); m/z (EI⁺ 70V) 349.

[0210] Intermediate 12

[0211] 2,3-Bis(propylsulphonyl)pyrazine

[0212] Propanethiol (1.99 ml, 22 mmol) was added to a suspension ofsodium hydride (60% in mineral oil, 880 mg, 22 mmol) in THF (50 ml).After 10 min, a solution of 2,3-dichloropyrazine (1.49 g, 10 mmol) inTHF (15 ml) was added and the mixture stirred at room temperatureovernight. The reaction was quenched with water and the solvent removedin vacuo. The residue was dissolved in EtOAc, washed with water, 10%NaOH solution and brine, dried (Na₂SO₄) and evaporated in vacuo to givea pale yellow oil (2.7 g). This was dissolved in DCM (100 ml) at 0°, andmCPBA (57-86%, ˜40 mmol, 12.1 g) was added in portions. The mixture wasstirred at room temperature overnight, then treated with NaSO₃ (aq). Theorganic phase was washed with NaHCO₃ (aq), dried (Na₂SO₄) and evaporatedin vacuo to give the title compound as a white solid (3.18 g): δH(CDCl₃) 8.94 (2H, s), 3.58-3.63 (4H, m), 2.10-1.88 (4H, m), 1.10 (6H, t,J 7.4 Hz); m/z (EI⁺, 70V) 293.

[0213] Intermediate 13

[0214] 4,6-Bis(propylsulphonyl)pyrimidine

[0215] The title compound was prepared by the method of Intermediate 12from 4,6-dichloropyrimidine: δH (DMSO d₆) 9.77 (1H, d, J 1.3 Hz), 8.40(1H, d, J 1.3 Hz), 3.61-3.56 (4H, m), 1.75-1.65 (4H, m), 0.97 (6H, t, J7.5 Hz); m/z (EI⁺, 70V) 293.

[0216] Intermediate 14

[0217] 2-Chloro-3-phenoxyguinoxaline

[0218] A solution of phenol (564 mg, 6 mmol) in THF (5 ml) was added toa suspension of sodium hydride (60% in mineral oil, 240 mg, 6 mmol) inTHF (10 ml). After 10 min 2,3-dichloroquinoxaline (995 mg, 5 mmol) wasadded. The mixture was stirred for 3 days. The solvent was removed invacuo, the residue was dissolved in EtOAc, washed with NaOH (1M), dried(Na₂SO₄) and evaporated in vacuo to give a yellow solid.Recrystallisation from diisopropylether gave the title compound asoff-white needles: δH (DMSO d₆) 8.01-7.98 (1H, m), 7.77-7.67 (3H, m),7.53-7.48 (2H, m), 7.37-7.30 (3H, m); m/z (EI⁺, 70V) 257.

[0219] Intermediate 15

[0220] Ethyl 2-(diethoxyphosphoryl)-3-(4-nitrophenyl)propionate

[0221] Ethyl 2-(diethoxyphosphoryl)acetate (5.0 ml, 25.2 mmol) was addedto a suspension of sodium hydride (60% in mineral oil, 1.10 g, 27.6mmol) in THF (40 ml) at 0°. After 30 min at room temperature, a solutionof 4-nitrobenzylbromide (5.42 g, 25.2 mmol) in THF (40 ml) was addedover 30 min. The reaction mixture was stirred for 2 h at roomtemperature, quenched with water and partitioned between Et₂O and water.The aqueous phase was extracted with Et₂O and the combined organiclayers washed with brine, dried (MgSO₄) and evaporated in vacuo. Columnchromatography (silica; MeOH/DCM, 1:49) gave the title compound as apale yellow oil (2.01 g): δH (CDCl₃) 8.13 (2H, d, J 8.8 Hz), 7.37 (2H,d, J 8.8 Hz), 4.23-4.06 (1H, m), 3.37-3.20 (3H, m), 1.35 (6H, t, J 7.1Hz), 1.16 (3H, t, J 7.1 Hz): m/z (EI⁻, 70V) 360.

[0222] Intermediate 16

[0223] Ethyl 3-(4-aminophenyl)-2-(diethoxyphosphoryl) Propionate

[0224] A mixture of Intermediate 15 (4.5 g, 12.0 mmol) and tin(II)chloride dihydrate (15 g) in ethanol was stirred overnight. The solventwas removed in vacuo. DCM (100 ml) and 1M NaOH (100 ml) was added andthe white precipitate removed by filtration. The organic phase of thefiltrate was separated and evaporated in vacuo. The residue wasacidified to pH1 with dil. HCl and extracted with diethyl ether. Theaqueous phase was basified to pH10 with Na₂CO₃ and extracted with EtOAc.The EtOAc extracts were dried (MgSO₄) and evaporated in vacuo. Columnchromatography (silica; MeOH/DCM 5:95) gave the title compound as ayellow oil (2.19 g): δH CDCl₃) 6.98 (2H, d, J 8.2 Hz), 6.59 (2H, d, J8.5 Hz), 4.22-4.04 (6H, m), 3.25-3.02 (3H, m), 1.34 (6H, m), 1.16 (3H,t, J 7.1 Hz): m/z (EI⁺, 70V) 330.

[0225] Intermediate 17

[0226] Ethyl3-[4-(3,5-Dichloropyrid-4-ylcarboxamido)phenyl]-2(diethoxyphosphoryl)Propionate

[0227] A solution of 3,5-dichloropyrid-4-ylcarbonyl chloride (1.41 g,6.7 mmol) in THF (10 ml) was added to a solution of Intermediate 16(2.19 g, 6.7 mmol) and NMM (0.88 ml, 8.0 mmol) in THF (40 ml). Themixture was stirred at room temperature overnight then partitionedbetween EtOAc and water. The aqueous layer was extracted with EtOAc andthe combined organic yers washed with 10% aqueous HCl and NaHCO₃ (aq),dried (MgSO₄) and evaporated in vacuo. Column chromatography (silica;MeOH/DCM 95) gave the title compound as a yellow oil (2.61 g): δH(CDCl₃) 8.55 (2H, s), 8.08 (1H, br. s), 7.55 (2H, d, J 8.5 Hz), 7.21(2H, d, J 8.5 Hz), 4.19-4.08 6H, m), 3.25-3.10 (3H, m), 1.35 (3H, t, J7.1 Hz), 1.34 (3H, t, J 7.1 Hz), 1.18 (3H, t, J 7.1 Hz).

[0228] Intermediate 18

[0229] Ethyl 2-[4-(3,5-dichloropyrid-4-ylcarboxamido)benzyl] Acrylate

[0230] A mixture of Intermediate 17 (1.74 g, 3.6 mmol), potassiumcarbonate (1.48 g, 10.7 mmol) and aqueous paraformaldehyde (37% wt, 10ml) was heated at reflux for 4 h. The mixture was partitioned betweenEtOAc and water. The aqueous phase was extracted with EtOAc and thecombined organic layers washed with brine, dried (MgSO₄) and evaporatedin vacuo. Column chromatography (silica; EtOAc/Hexane 50:50) gave thetitle compound as a white solid (1.09 g): δH (CDCl₃) 8.52 (1H, br. s),8.44 (2H, br. s), 7.49 (2H, d, J 8.5 Hz), 7.18 (2H, d, J 8.5 Hz), 6.22(1H, br. s), 5.49 1H, br. s), 4.15 (2H, q, J 7.2 Hz), 3.60 (2H, br. s),1.27 (3H, t, J 7.2 Hz).

[0231] Intermediate 19

[0232] Ethyl 3-amino-2-[4-(3.5-dichloropyrid-4-ylcarboxamido)benzyl]Propionate

[0233] A mixture of Intermediate 18 (1.50 g, 3.7 mmol) and liquidammonia (10 ml) was kept in a sealed vessel for 3 d at room temperature.Column chromatography (silica; MeOH/DCM 1:9 to 1:4) gave the titlecompound as a colourless oil (1.00 g): δH (DMSO d₆) 10.83 (1H, s), 8.78(2H, d, J 8.5 Hz), 7.54 (2H, d, J 8.5 Hz), 7.16 (2H, d, J 8.5 Hz), 4.00(2H, q, J 7.1 Hz), 3.29 (2H, br. s), 2.83-2.61 (5H, m), 1.10 (3H, t, J7.1 Hz): m/z (EI⁺, 70V) 396.

[0234] Intermediate 20

[0235] Ethyl 2-diazo-3-[4-(3.5-dichloropyrid-4-ylcarboxamido)phenyl]Propionate

[0236] A solution of the compound of Intermediate 3 (free amine) (2.80g, 7.40 mmol), glacial acetic acid (1.4 ml, 24.50 mmol), isoamyl nitrite(1 ml, 7.40 mmol) in 100 ml anhydrous chloroform were stirred at refluxunder nitrogen for 1 h. On cooling the solution was washed with water(2×25 ml), saturated NaHCO₃ (2×25 ml), water (2×25 ml), dried (Na₂SO₄)and evaporated in vacuo to afford the title compound as a yellow solid(2.1 g, 100%): δH (CDCl₃) 8.56 (2H, s), 7.72 (1H, br. s), 7.55 (2H, d, J8.5 Hz), 7.26 (2H, d, J 8.5 Hz), 4.22 (2H, q,J 7.1 Hz), 3.62 (2H, s),1.25 (3H, t, J 7.1 Hz).

[0237] Intermediate 21

[0238] 5-Chloro-2-(2,5-dimethylpyrrol-1-yl)-pyridine

[0239] 2-Amino-5-chloropyridine (10.0 g, 77 mmol), acetonyl acetone (8.8g, 77 mmol) and a catalytic amount of p-toluenesulphonic acid inanhydrous toluene (250 ml) was heated to reflux for 5 h under Dean andStark conditions. The solvent was-removed in vacuo, the residue slurriedin hexane (250 ml), filtered through celite and the solvent removed invacuo to give the title compound as a yellow oil (16.0 g): δH (CDCl₃)8.57 (1H, dd, J 2.7, 0.6 Hz), 7.78 (1H, dd, J 8.4, 2.7 Hz), 7.17 (1H, m,J 7.5, 0.5 Hz), 5.91 (2H, s), 2.14 (6H, s).

[0240] Intermediate 22

[0241] 5-Chloro-4-propylthio-2-(2.5-dimethylpyrrol-1-yl)-pyridine

[0242] To a solution of LDA (12.3 mmol) in anhydrous toluene (6 ml) at−78° under nitrogen was added Intermediate 21-(2.3 g, 11.2 mmol) in THF(6 ml) dropwise over 15 min. After stirring a further 15 min at thistemperature n-propyl disulfide (1.92, 12.8 mmol) in THF (2 ml) was addeddropwise maintaining the temperature at −780. On completion of theaddition the reaction was allowed to warm to room temperature andquenched with 10% N₄Cl solution, diluted with EtOAc (50 ml) and thephases separated. The organic phase was washed with water (2×10 ml),dried (MgSO₄) and the solvent removed in vacuo. The residue was purifiedby chromatography (silica; 2% EtOAc/Hexane) to give the title compound(2.9 g) as a yellow solid: δH (CDCl₃) 8.39 (1H, s), 7.00 (1H, s), 5.92(2H, s), 2.91 (2H, d, J 7.4 Hz), 2.15 (6H, s), 1.74 (2H, m), 1.09 (3H,t, J 7.4 Hz).

[0243] Intermediate 23

[0244] 2-Amino-5-Chloro-4-propylthiopyridine

[0245] Intermediate 22 (1.3 g, 4.6 mmol) and hydroxylamine hydrochloride(1.6 g, 23 mmol) were heated to reflux in EtOH (12 ml) and water (3.5ml) for 16 h. The cooled solution was poured onto conc HCl (12 ml)/water(48 ml) and the resulting solid filtered, washed with water and dried togive the title compound as a brown solid (550 mg): δH (CDCl₃) 8.11 (1H,s), 6.91 (1H, s), 3.01 (2H, t, J 7.3 Hz), 1.64 (2H, m), 1.00 (3H, t, J7.3 Hz)): m/z (EI⁺, 70V) 203.

[0246] Intermediate 24

[0247] Resin Bound(S)-2-(9-Fluorenylmethoxycarbonylamino)-3-[4-(3,5-dichloropyrid-4-ylcarboxamido)phenyl]propanoic Acid

[0248] Paramax Wang resin (Advanced Chemtech, 8.0 g, 0.69 mmol/g, 5.52mmol equivalent) in DCM (100 ml) was treated withN-α-FMOC-4-nitro-L-phenylalanine (11.93 g, 27.6 mmol),diisopropylcarbodiimide (4.32 ml, 27.6 mmol) and4-N,N-dimethylaminopyridine (0.67 g, 5.52 mmol) and mixture was agitatedat room temperature for 16 h. The resin was filtered and washed withDMF, methanol and DCM, then air-dried. The resin was then treated withstannous chloride dihydrate (12.5 g, 55.2 mmol) in DMF (100 ml) at roomtemperature for 6 h, washed with DMF, methanol and DCM, then air driedovernight. The resin was treated with pyridine (4.44 ml, 55.2 mmol),3,5-dichloropyrid-4-carbonyl chloride 3.52 g, 16.56 mmol) and4-N,N-dimethylamino pyridine (0.67 g, 5.52 mmol) in DCM (100 ml). Thereaction mixture was agitated at room temperature for 16 h. The resinwas then washed with DMF, methanol and DCM, then with two 50 ml portionsof a 10% solution of pyridine in DMF (100 ml). The resin was furtherwashed with hot ethanol (2×100 ml), DMF, methanol and DCM then air-driedto give the title compound.

[0249] Intermediate 25

[0250] Resin Bound3-[4-(3,5-dichloropyrid-4-ylcarboxamido)phenyl]-2-diazopropanoic Acid

[0251] A portion of Intermediate 24 (3.0 g) was treated twice with a 20%solution of piperidine in DMF (100 ml), once for 5 min and once for 15min. The resin was washed with DMF, methanol and DCM. This material wastreated with isoamyl nitrite (1.79 ml, 12.30 mmols) and acetic acid(0.074 ml, 1.23 mmols) in anhydrous chloroform (70 ml) for 1 hr, thenfiltered and washed with DMF, methanol and DCM then finally air dried togive the title compound.

EXAMPLE 1

[0252]S-Methyl-3-[4-(3,5-dichloropyrid-4-ylcarboxamido)phenyl]-2-(4.6-dimethoxy-1.3.5-triazin-2-ylamino)propionate

[0253] A solution of Intermediate 4 (330 mg, 0.90 mmol), DIPEA (163 μl,121 mg, 0.94 mmol), and 2-chloro-4,6-dimethoxy-1,3,5-triazine (233 mg,1.32 mmol) in MeOH (2 ml) was stirred under gentle reflux for 7 h underN₂. The volatiles were removed in vacuo and the residue partitionedbetween EtOAc (80 ml) and saturated aqueous NaHCO₃ (30 ml). The phaseswere separated and the aqueous layer re-extracted with EtOAc (40 ml).The combined organic extracts were washed with brine (10 ml), dried(Na₂SO₄) and evaporated in vacuo to afford a straw-coloured oil.Chromatography (silica; 4% MeOH/DCM) afforded the title compound as acolourless foam (330 mg, 73%): δH (CDCl₃) 8.46 (2H, s), 8.32 (1H, s),7.51 (2H, d, J 84 Hz), 7.12 (2H, d, J 8.4 Hz), 6.17 (2H, d, J 8.0 Hz),5.00 (1H, d, J 13.8, 6.0 Hz), 3.92 (3H, s), 3.89 (3H, s) and 3.75 (3H,s); m/z (EI⁺, 160V) 507, 509.

EXAMPLE 2

[0254]S-3-[4-(3,5-Dichloropyrid-4-ylcarboxamido)phenyl]-2-(4.6-dimethoxy-1,3,5-triazin-2-ylamino)propanoicAcid

[0255] A solution of the compound of Example 1 (300 mg, 0.59 mmol) andLiOH.H₂O (0.88 mmol) in dioxane (2 ml), MeOH (1 ml) and water (2 ml) wasstirred at room temperature for 1 h. The pH was made acidic with a fewdrops of AcOH and the volatiles removed in vacuo. The residue waschromatographed [silica; DCM (400->200), MeOH (20), AcOH (3), H₂O (2))affording the product as a colourless oil. Freeze drying from aqueousMeOH gave the title compound as a white amorphous solid (215 mg, 76%).δH (d₆ DMSO) 10.84 (1H, s), 8.77 (2H, s), 8.10 (1H, d, J 8.0 Hz), 7.54(2H, d, J 8.4 Hz), 7.29 (2H, d, J 8.4 Hz), 4.58-4.48 (1H, m), 3.80 (3H,s), 3.78 (3H, s), 3.12 (1H, dd, J 14.0, 4.7 Hz) and 2.98 (1H, dd, J 14,10.2 Hz). m/z (EI⁺100V), 493, 495, 497.

EXAMPLE 3

[0256] S-Ethyl3-[4-(3.5-dichloropyrid-4-ylcarboxamido)phenyl]-2-(6-chloropyrimidin-4-ylamino)propionate

[0257] 3,5-Dichloropyrid-4-carbonyl chloride (289 mg, 1.37 mmol) wasadded to a stirred solution of Intermediate 9 (400 mg, 1.25 mmol) andNMM (150 μl, 139 mg, 1.37 mmol) in dry DCM (10 ml). After stirring for 1h at room temperature under N₂, the reaction mixture was partitionedbetween DCM (70 ml) and saturated aqueous NaHCO₃ (30 ml). The phaseswere separated and the aqueous layer re-extracted with DCM (50 ml). Thecombined organic extracts were washed with brine (10 ml), dried (Na₂SO₄)and evaporated in vacuo. The obtained orange oil was chromatographed(silica; 5% MeOH/DCM) to afford the title compound as a straw-colouredfoam (504 mg, 82%); δH (CDCl₃,) 8.48 (2H, s), 8.41 (1H, s), 8.32 (1H,s), 7.48 (2H, d, J 8.4 Hz), 7.08 (21H, d, J 8.4 Hz), 6.38 (1H, s), 5.72(1H, br s), 4.96 (1H, br s), 4.22 (2H, q, J 7.1 Hz), 3.25 (1H, dd, J14.0, 5.5 Hz), 3.14 (1H, dd, J 14.0, 5.8 Hz) and 1.21 (3H, t, J 1.1 Hz);m/z (EI⁺, 160V) 496.

EXAMPLE 4

[0258]S-3-[4-(3.5-Dichloropyrid-4-ylcarboxamido)phenyl]-2-(6-chloropyrimidin-4-ylamino)propanoicAcid

[0259] A solution of Example 3 (475 mg, 0.96 mmol) and LiO.H₂O (40 mg,0.96 mmol) in dioxane (5 ml), MeOH (3 ml) and water (3 ml) was stirredat room temperature for 2.5 h. A few drops of AcOH were added and thevolatiles removed in vacuo. The residue was chromatographed [silica; DCM(200), MeOH (20), AcOH (3), H₂O (2)] to afford the product as a slightlyyellow oil. The oil was dissolved in a small volume of MeOH, dilutedwith water and freeze-dried to give the title compound as an off-whiteamorphous solid (290 mg, 65%); Found: C, 47.67; H, 2.9; N, 14.65.C₁₉H₁₄Cl₃N₅O₃.0.66H₂O requires C, 47.67; H, 3.23; N, 14.63%. δH (d₆DMSO) 10.86 (1H, s), 8.78 (2H, s), 8.26 (1H, s), 7.98 (1H, br d, J 7.6Hz), 7.55 (2H, d, J 8.2 Hz), 7.25 (2H, d, J 8.2 Hz), 6.66 (1H, s), 4.76(1H, br s), 3.16 (1H, dd, J 13.9, 4.7 Hz) and 2.98 (1H, dd, J 13.9, 8.9Hz); m/z (EI⁺, 160V) 468.

EXAMPLE 5

[0260] S-Ethyl3-[4-(3.5-dichloropyrid-4-ylcarboxamido)]phenyl]-2-(6-propylthiopyrimidin-4-ylaminopropionate

[0261] A solution of Intermediate 3 (2.0 g, 4.8 mmol), DIPEA (1.29 g,1.74 ml, 10 mmol) and 4-chloro-6-propylthio-pyrimidine (1.08 g, 5.7mmol) in 2-ethoxyethanol (8 ml) was heated at 110° for 2 days and 130°for 2 days under nitrogen. The volatiles were removed in vacuo and thedark oil partitioned between EtOAc (100 ml) and 5% aqueous citric acid(40 ml). The phases were separated and the aqueous layer re-extractedwith EtOAc (2×30 ml). The combined organic extracts were washedconsecutively with saturated aqueous NaHCO₃ (20 ml), water (20 ml),brine (20 ml), dried (Na₂SO₄) and treated with activated carbon,filtered and evaporated in vacuo. The obtained oil was purified bychromatography (silica; 2-3% MeOH/DCM) to afford the title compound(together with 20% of the ethoxyethyl ester analogue) as a pale yellowfoam (1.26 g, 49%): δH (CDCl₃) 8.56 (2H, s), 8.38 (1H, s), 7.68 (1H, s),7.53 (2H, d, J 8.6 Hz), 7.13 (2H, d, J 8.6 Hz), 6.20 (1H, s), 5.23-5.12(1H, m), 5.00-4.84 (1H, m), 4.21 (2H, q, J 7.1 Hz), 3.26 (1H, dd, J14.0, 5.3 Hz), 3.15 (1H, dd, J 14.0, 5.7 Hz), 3.06 (2H, t, J 7.3 Hz),1.71 (2H, hex, J 7.3 Hz), 1.29 (3H, t, J 7.1 Hz), 1.04 (3H, t, J 7.3Hz); m/z (EI⁺, 100V) 520.

EXAMPLE 6

[0262] S-Ethyl3-[4-(3,5-dichloropyrid-4-ylcarboxamido)-phenyl]-2-(6-propylsulphonylpyrimidin-4-ylamino)propionate

[0263] mCPBA (assumed 60% pure, 1.43 g, 4.96 mmol) was added to asolution of the compound of Example 5 (1.26 g, 2.36 mmol) in dry DCM (20ml), and stirred at room temperature for 4 h. 10% aqueous sodiumsulphite (20 ml) was added and stirred for 5 min. After diluting withDCM (130 ml) and shaking, the phases were separated. The organic phasewas washed consecutively with saturated aqueous NaHCO₃ (3×30 ml), water(25 ml) and brine (10 ml), dried (Na₂SO₄) and evaporated in vacuo.Chromatography (silica; 2% MeOH/DCM) afforded the title compound as apale yellow foam (640 mg, 50%): δH (CDCl₃) 8.63 (1H, s), 8.50 (2H, s),8.05 (1H, s), 7.47 (2H, d, J 8.6 Hz), 7.10 (2H, d, J MHz), 6.22-6.13(1H, br. m), 5.18-5.08 (1H, br. m), 4.24 (2H, q, J 7.4 Hz), 3.32-3.25(2H, m), 3.17 (1H, dd, J 14.1, 6.2 Hz), 1.75 (2H, hex, J 7.4 Hz), 1.31(3H, t, J 7.1 Hz), 1.03 (3H, t, J 7.4 Hz); m/z (EI⁺, 100V) 566.

EXAMPLE 7

[0264]S-3-[4-(3.5-Dichloropyrid-4-ylcarboxamido)-phenyl]-2-(6-propylsulphonylpyrimidin-4-ylamino)propanoicAcid

[0265] The title compound (395 mg, 66%) was prepared from the compoundof Example 6 (630 mg, 1.11 mmol) by hydrolysis in a similar manner toExample 2: δH (DMSO d₆) 10.85, (1H, s), 8.77 (2H, s), 8.56 (1H, s), 8.44(1H, d, J 7.8 Hz), 7.55 (2H, d, J 8.4 Hz), 7.26 (2H, d, J 8.4 Hz), 7.22(1H, s), 4.85-4.72 (1H, br. m), 3.33 (2H, t, J 7.6 Hz), 3.18 (1H, dd, J13.8, 4.7 Hz), 2.99 (1H, dd, J 13.8, 9.1 Hz), 1.59 (2H, hex, J 7.6 Hz),0.93 (3H, t, J 7.6 Hz); m/z (EI⁺, 70V) 538.

EXAMPLE 8

[0266] S-Ethyl3-[4-(3.5-dichloropyrid-4-ylcarboxamido)-phenyl]-2-(6-propylsulphinylpyrimidin-4-ylamino)propionate

[0267] mCPBA (assumed 86% pure, 223 mg, 1.11 mmol) was added to anice-bath cooled solution of the compound of Example 5 (500 mg, 0.94mmol) in dry DCM (15 ml), and stirred for 1 h with cooling and for 2 hat room temperature. 10% aqueous sodium sulphite (10 ml) and DCM (100ml) was added and the mixture vigorously stirred for 5 min. The phaseswere separated and the organic phase was washed consecutively withsaturated aqueous NaHCO₃ (2×30 ml), water (10 ml) and brine (10 rnl),dried (Na₂SO₄) and evaporated in vacuo. Chromatography (silica; 2-3%MeOH/DCM) afforded the title compound as a mixture of diastereoisomerstogether with a small amount of the corresponding ethoxyethyl analogue(330 mg, 64%): δH (CDCl₃) 8.82-8.80 (1H, s), 8.49-8.45 (3H, s),7.53-7.47 (2H, overlapping d's, J 8.6 Hz), 7.17-7.08 (2H, overlappingd's J 8.6 Hz), 7.01-6.95 (1H, s), 6.31-6.22 (1H, m), 5.20-5.00 (1H, br.m), 4.30-4.15 (2H, overlapping q's, J 7 Hz), 3.87-3.12 (2H, br. m),3.10-3.01 (1H, br. m), 2.87-2.70 (1H, br. m), 1.92-1.74 (1H, br. m),1.69-1.50 (1H, br. m), 1.33-1.20 (3H, t, J 7 Hz), 1.08-0.99 (3H,overlapping t's, J 7 Hz); m/z (EI⁺, 70V) 550.

EXAMPLE 9

[0268]S-3-[4-(3,5-Dichloropyrid-4-ylcarboxamido)-phenyl]-2-(6-propylsulphinylpyrimidin-4-ylamino)propanoicAcid

[0269] The title compound as a 1:1 mixture of diastereoisomers (278 mg,92%) was prepared from the compound of Example 8 (320 mg, 0.58 mmol) byhydrolysis in a similar manner to Example 2; δH (DMSO d₆) 10.85 (1H, s),8.77 (2H, s), 8.40 (1H, s), 8.25 (1H, d, J 7.6 Hz), 7.55 (2H, d, J 8.3Hz), 7.30-7.20 (2H, m), 7.09 (1H, s), 4.82-4.69 (1H, m), 3.17 (1H, dd, J14, 4 Hz), 3.12-2.90 (2H, br. m), 2.85-2.72 (1H, m), 1.80-1.62 (1H, m),1.55-1.37 (1H, m), 1.01-0.90 (3H, overlapping t's); m/z (EI⁺, 70V) 522.

EXAMPLE 10

[0270] S-Ethyl3-[4-(3,5-dichloropyrid-4-ylcarboxamido)-phenyl]-2-(6-benzylthiopyrimidin-4-ylamino)propionate

[0271] A solution of Intermediate 3 (1.0 g, 2.39 mmol), DIPEA (647 mg,872 μl, 5 mmol) and 4-benzylthio-6-chloro-pyrimidine (678 mg, 2.87 mmol)in 2-ethoxyethanol (4 ml) was heated at 120° for 58 h. The volatileswere removed in vacuo and the residue worked up in a manner analogous tothat described for Example 5. The crude product was chromatographed(silica; 2-3% MeOH/DCM) to afford the title compound (together with someof the ethoxyethyl ester analogue) as a near colourless glassy solid(560 mg, 40%): δH (CDCl₃) 8.55 (2H, s), 8.42 (1H, s), 7.73 (1H, s), 7.51(2H, d, J 8.4 Hz), 7.39-7.24 (m, 5H), 7.11 (2H, d, J 8.4 Hz), 6.19 (1H,s), 5.27-5.18 (1H, m), 4.95-4.81 (1H, m), 4.37 (2H, s), 4.21 (2H, q, J7.1 Hz), 3.21 (1H, dd, J 14.0, 5.0 Hz), 3.15 (1H, dd, J 14.0, 5.7 Hz),1.28 (3H, t, J 7.1 Hz); m/z (EI⁺, 70V) 582.

EXAMPLE 11

[0272]S-3-[4-(3,5-Dichloropyrid-4-ylcarboxamido)phenyl]-2-(6-benzylthiopyrimidin-4-ylamino)propanoicAcid

[0273] The title compound was prepared from the compound of Example 10by hydrolysis in a similar manner to Example 2: δH (DMSO d₆, 390K) 10.84(1H, br. s), 8.77 (2H, s), 8.24 (1H, s), 7.55-7.25 (7H, m), 6.46 (1H,s), 4.66 (1H, m), 4.31 (2H, s), 3.13-2.90 (2H, m); m/z (EI⁺, 70V) 554.

EXAMPLE 12

[0274] S-Ethyl3-[3-Chloro-4-(3.5-dichloropyrid-4-ylcarboxamido)-phenyl]-2-(6-diethylaminosulphonylpyrimidin-4-ylamino)propionateand S-Ethyl3-[3.5-dichloro-4-(3,5-dichloropyrid-4-ylcarboxamido)-phenyl]-2-(6-diethylaminosulphonylpyrimidin-4-ylamino)propionate

[0275] Chlorine gas was bubbled through a vigorously stirred ice-bathcooled mixture of the compound of Example 10 (550 mg), DCM (8 ml) and10% aqueous HCl (20 ml). The cooled reaction mixture was then stirredfor an additional 30 min. Excess chlorine was removed by purging withnitrogen and the reaction mixture diluted with DCM (70 ml). The phaseswere shaken, separated and the aqueous phase re-extracted with DCM (30ml). The combined organic extracts were treated with diethylamine (2 ml)and left to stand for 45 min. The volatiles were removed in vacuo andthe residue partitioned between EtOAc (70 ml) and water (20 ml). Thephases were separated and the aqueous phase re-extracted with EtOAc(2×15 ml). The combined organic extracts were washed with brine (10 ml),dried (MgSO₄) and evaporated in vacuo. The obtained dark foam waschromatographed twice (silica; 2% MeOH/DCM then 25% Et₂O/DCM) affordinga 2:1 mixture of the title compounds (240 mg): δH (CDCl₃) 8.62 (1H, s),8.59 (2H×0.66, s), 8.57 (2H×0.33, s), 8.31 (1H×0.66, s), 7.85 (1H×0.33,s), 7.20 (2H×0.33, s), 7.11 (1H×0.66, d, J 8.4 Hz), 5.84-5.72 (1H, br.m), 5.18-4.95 (1H, br. m), 4.26 (2H, q, J 7.1 Hz), 3.3) (2H, q, J 7.1Hz), 3.28 (1H, dd, J 14.0, 5.3 Hz), 3.17 (1H, dd, J 14.0, 5.6 Hz), 1.32(3H×0.33, t, J 7.1 Hz), 1.30 (3H×0.66, t, J 7.1 Hz), 1.17 (6H, t, J 7.1Hz); m/z (EI⁺, 70V) 531 and 665.

EXAMPLE 13

[0276]S-3-[3-Chloro-4-(3.5-dichloropyrid-4-ylcarboxamido)-phenyl]-2-(6-diethylaminosulphonylpyrimidin-4-ylamino)propanoicAcid andS-3-[3.5-dichloro-4-(3.5-dichloropyrid-4-ylcarboxamido)-phenyl]-2-(6-diethylaminosulphonylpyrimidin-4-ylamino)propanoicAcid

[0277] The mixture of compounds of Example 12 (240 mg, 0.38 mmol) wastreated with a solution of LiOH.2H₂O (27 mg, 0.64 mmol) in dioxan (3 ml)and water (3 ml) at room temperature for 2.5 h. A few drops of aceticacid were added and the volatiies were removed in vacuo. The residue waschromatographed several times (silica; DCM (400-200), MeOH (20), AcOH(3), H₂O (2)) to separate the two title compounds, affording afterfreezedrying from aqueous methanol, the less polarS-3-[3-Chloro-4-(3.5-dichloropyrid-4-ylcarboxamido)-phenyl]-2-(6-diethylaminosulphonylpyrimidin-4-ylamino)propanoic acid as a white amorphous solid (105 mg,49%): δH (DMSO d₆) 10.61 (1H, s), 8.75 (2H, s), 8.50 (1H, s), 8.31 (1H,d, J 7.8 Hz), 7.62,(1H, d, J 8.1 Hz), 7.43 (1H, s), 7.28 (1H, d, J 8.1Hz), 7.10 (1H, s), 4.83-4.75 (1H, m), 3.26 (4H, t, J 7.1 Hz), 3.22 (1H,m), 3.05 (1H, dd, J 13.8, 9.1 Hz), 1.05 (6H, t, J 7.1 Hz); m/z (ES⁺,70V) 603; and the more polarS-3-[3,5-dichloro-4-(3.5-dichloropyrid-4-ylcarboxamido)-phenyl]-2-(6-diethylaminosulphonylpyrimidin-4-ylamino)propanoicacid as a white amorphous solid (49 mg, 21%): δH (DMSO d₆) 10.83 (1H,s), 8.76 (2H, s), 8.50 (1H, s), 8.29 (1H, d, J 7.8 Hz), 7.44 (2H, s),7.12 (1H, s), 4.85-4.74 (1H, m), 3.26 (4H, t, J 7.1 Hz), 3.20 (1H, m),3.05 (1H, dd, J. 13.8, 9.9 Hz), 1.05 (6H, t, J 7.1 Hz); m/z (EI⁺, 70V)637.

EXAMPLE 14

[0278] S-Ethyl3-[3-Chloro-4-(3.5-dichloropyrid-4-ylcarboxamido)-phenyl]-2-(6-propylaminosulphonylpyrimidin-4-ylamino)propionate

[0279] The title compound (430 mg) was prepared in an analogous mannerto the compound of Example 12 starting from the compound of Example 10(500 mg) and using n-propylamine: δH (CDCl₃) 8.63 (1H, s), 8.60 (2H, s),8.45 (1H, s), 8.32 (1H, d, J 7.8 Hz), 7.88 (1H, s), 7.25-6.98 (3H ,m),6.02-5.90 (1H, m), 5.13-5.06 (1H, m), 4.28 (2H, q, J 7.1 Hz), 3.38-3.15(2H, m), 3.04 (2H, q, J 7.1 Hz), 1.53 (2H, q, J 7.1 Hz), 1.24 (3H, t, J7.1 Hz), 0.97 (3H, t, J 7.1 Hz); m/z (EI⁺, 70V) 627.

EXAMPLE 15

[0280]S-3-[3-Chloro-4-(3,5-dichloropyrid-4-ylcarboxamido)-phenyl]-2-(6-propylaminosulphonylpyrimidin-4-ylamino)propanoicAcid

[0281] The title compound (151 mg, 66%) was prepared from the compoundof Example 14 (394 mg, 0.60 mmol) by hydrolysis in a similar manner toExample 2: 6H (DMSO d₆) 10.61 (1H, s), 8.76 (2H, s), 8.51 (1H, s), 8.32(1H, d, J 7.8 Hz), 7.80 (1H, t, J 5.7 Hz). 7.63 (1H, d, J 8.3 Hz), 7.45(1H, s), 7.29 (1H, d, J 8.3 Hz), 7.10 (1H, s), 4.85-4.74 (1H, m), 3.22(1H, dd, J 13.9, 4.9 Hz), 3.02 (1H, dd, J 13.9, 9.0 Hz), 2.86 (2H, t, J6.8 Hz), 1.38 (2H, hex, J 6.8 Hz), 0.79 (3H, t, J 7.3 Hz); m/z (EI⁺,70V) 589.

EXAMPLE 16

[0282]S-3-[4-(3.5-Dichloropyrid-4-ylcarboxamido)-phenyl]-2-(6-methoxy-2-methylsulphonylpvrmidin-4-ylamino)propanoicAcid

[0283] The title compound was prepared from Intermediate 3 and2,4-di-(methylsulphonyl)-6-methoxypyrimidine by a method similar to thatdescribed for Intermediate 10 followed by ester hydrolysis according tothe method of Example 2: δH (DMSO d₆) 12.70 (1H, br. s), 10.84 (1H, s),8.77 (2H, s), 8.23 (d, J 7.6 Hz) and 8.08 (d, J 7.7 Hz) together (1H),7.54 (2H, d, J 8.0 Hz), 7.33 (2H, d, J 8.0 Hz), 6.48 (1H, s), 4.55-4.46(1H, m), 3.89 (s) and 3.86 (s) together (3H), 3.20-3.03 (2H, m); m/z(EI⁺, 70V) 540.

EXAMPLE 17

[0284]S-3-[4-(3.5-Dichloropyrid-4-ylcarboxamido)-phenyl]-2-(6-methoxy-2-propylsulphonylpyrimidin-4-ylamino)propanoicAcid

[0285] The title compound was prepared from Intermediate 3 and 2,4-din-propylsulphonyl-6-methoxypyrimidine by a method similar to thatdescribed for Intermediate 10 followed by ester hydrolysis according tothe method of Example 2: δH (DMSO d₆) 12.69 (1H, br.s), 10.83 (1H, s),8.77 (2H, s), 8.18 (d, J 7.9 Hz) and 8.06 (d, J 7.9 Hz) together (1H),7.54 (2H, d, J 8.2 Hz), 7.32 (2H, d, J 8.2 Hz), 6.48 (s) and 6.47 (s)together (1H), 4.554.42 (1H, m), 3.89 (s) and 3.86 (s) together (3H),3.29 (2H, q, J 7.7 Hz), 3.12 (1H, dd, J 13.9, 4.6 Hz), 3.02 (1H, dd, J13.9, 9.9 Hz), 1.68-1.49 (2H, m), 0.94 (t, J 7.2 Hz) and 0.92 (t, J 7.2Hz) together (3H); m/z (EI⁺, 70V) 568 and 570.

EXAMPLE 18

[0286]S-3-[4-(3,5-Dichloropyrid-4-ylcarboxamido)-phenyl]-2-(4-trifluoromethylpyrimidin-2-ylamino)propanoicAcid

[0287] The title compound was prepared from Intermediate 3 and2-chloro-4-(trifluoromethyl)pyrimidine, followed by hydrolysis: δH (DMSOd₆) 12.70 (1H, br.s), 10.83 (1H, s), 8.77 (2H, s), 8.58 (1H, d, J 4.9Hz), 8.15 (d, J 8.0 Hz) and 8.06 (d, J 8.0 Hz) together (1H), 7.54 (2H,d, J 8.2 Hz), 7.33 (2H, d, J 8.2 Hz), 6.99 (1H, d, J 4.9 Hz), 4.62-4.42(1H, br. m), 3.15 (1H, dd, J 13.7, 4.4 Hz), 3.10-2.95 (1H, m) m/z (EI⁺,60V) 500 and 502.

EXAMPLE 19

[0288]S-3-[4-(3,5-Dichloropyrid-4-ylcarboxamido)-phenyl]-2-(6-phenoxypyrimidin-4-ylamino)propanoicAcid

[0289] The title compound was prepared from Intermediate 3 and4-chloro-6-phenoxypyrimidine, followed by hydrolysis: δH (DMSO d₆) 10.85(1H, s), 8.77 (2H, s), 8.12 (1H, s), 7.60 (1H, br. d, J 8.0 Hz), 7.54(2H, d, J 8.3 Hz), 7.41 (2H, t, J 7.8 Hz), 7.27-7.20 (3H, m), 7.12 (2H,d, J 8.2 Hz), 5.88 (1H, s), 4.80-4.60 (1H, br. m), 3.12 (1H, dd, J 13.8,4.7 Hz), 2.90 (1H, dd, J 13.8, 9.5 Hz); m/z (EI⁺, 60V) 524 and 526.

EXAMPLE. 20

[0290]S-3-[4-(3.5-Dichloropyrid-4-ylcarboxamido)-phenyl]-2-(2-methylthiopyrimidin-4-ylamino)propanoicAcid

[0291] The title compound was prepared from Intermediate 3 and4-chloro-2-methylthiopyrimidine followed by hydrolysis: δH (DMSO d₆)10.83 (1H, s), 8.77 (2H, s), 7.85 (1H, d, J 5.7 Hz), 7.71 (1H, br. s),7.54 (1H, d, J 8.5 Hz), 7.25 (1H, d, J 8.5 Hz), 6.28 (1H, d, J 5.7 Hz),4.70-4.53 (1H, br. m), 3.12 (1H, dd, J 14.0, 8.0 Hz), 2.96 (1H, dd, J14.0, 8.0 Hz); m/z (EI⁺, 60V) 478.

EXAMPLE 21

[0292]S-3-[4-(3.5-Dichloropyrid-4-ylcarboxamido)-phenyl]-2-(5-carboxy-2-methylthiopyrimidin-4-ylamino)propanoicAcid

[0293] The title compound was prepared from Intermediate 3 and ethyl4-chloro-2-methylthiopyrimidine-5-carboxylate, followed by hydrolysis:δH (DMSO d₆) 10.87 (1H, s), 9.01 (1H br. s), 8.77 (2H, s), 8.49 (1H, s),7.55 (2H, d, J 8.4 Hz), 7.20 (2H, d, J 8.4 Hz), 4.90-4.80 (1H, m), 3.21(1H, dd, J 13.8, 5.2 Hz), 3.09 (1H, dd, J 13.8, 6.9 Hz), 2.44 (3H, s);m/z (EI⁺, 60V) 522.

EXAMPLE 22

[0294]S-3-[4-(3,5-Dichloropyrid-4-ylcarboxamido)-phenyl]-2-(5-ethoxycarboxy-2-methylthiopyrimidin-4-ylamino)propanoicAcid

[0295] The title compound was prepared from Intermediate 3 and ethyl4-chloro-2-methylthiopyrimidine-5-carboxylate with subsequent partialhydrolysis of the coupled product: δH (DMSO d₆) 10.84 (1H, br. s), 8.77(2H, s), 8.55 (1H, s), 8.47 (1H, d, J 6.8 Hz), 7.54 (2H, d, J 8.3 Hz),7.18 (2H, d, J 8.3 Hz), 4.94-4.83 (1H, m), 4.25 (2H, q, J 7.1 Hz), 3.25(1H, dd, J 13.8, 5.3 Hz), 3.13 (1H, dd, J 13.8, 6.8 Hz), 2.46 (3H, s),1.26 (3H, t, 17.1 Hz); m/z (EI⁺, 60V) 550.

EXAMPLE 23

[0296]S-3-[4-(3,5-Dichloropyrid-4-ylcarboxamido)-phenyl]-2-(3-nitropyrid-2-ylamino)propanoicAcid

[0297] The title compound was prepared from Intermediate 3 and2-chloro-3-nitropyridine, followed by hydrolysis: δH (DMSO d₆) 10.86(1H, s), 8.77 (2H, s), 8.49-8.43 (2H, m), 8.29 (1H, d, J 7.0 Hz), 7.55(2H, d, J 8.5 Hz), 7.22 (2H, d, J 8.5 Hz), 6.84 (1H, dd, J 8.3, 4.5 Hz),5.03-4.99 (1H, m), 3.30-3.15 (2H, m); m/z (EI⁺, 60V) 476 and 478.

EXAMPLE 24

[0298]S-3-[4-(3,5-Dichloropyrid-4-ylcarboxamido)-phenyl]-2-(5-nitropyrid-2-ylamino)propanoicAcid

[0299] The title compound was prepared from Intermediate 3 and2-chloro-5-nitropyridine, followed by hydrolysis: δH (DMSO d₆) 10.84(1H, s), 8.85 (1H, d, J 2.6 Hz), 8.76 (2H, s), 8.32 (1H, d, J 7.4 Hz),8.10 (1H, dd, J 9.4, 2.6 Hz), 7.54 (2H, d, J 8.3 Hz), 7.26 (2H, d, J 8.3Hz), 6.69 (1H, d, J 9.4 Hz), 4.81 (1H, br. m), 3.19 (1H, dd, J 13.9, 4.7Hz), 3.00 (1H, dd, J 13.9, 9.2 Hz); m/z (EI⁺, 60V) 476 and 478.

EXAMPLE 25

[0300]S-3-[4-(3.5-Dichloropyrid-4-ylcarboxamido)-phenyl]-2-(6-propylthiopyrimidin-4-ylamino)propanoicAcid

[0301] The title compound was prepared by hydrolysis of the compound ofExample 5: δH (DMSO d₆)10.83 (1H, br. s), 8.77 (2H, s), 8.21 (1H, s),7.54 (2H, d, J 8.4 Hz), 7.24 (2H, d, J 8.4 Hz), 6.43 (1H, br. s), 4.67(1H, br. s), 3.13 (1H, dd, J 13.9, 4.8 Hz)), 3.00-2.90 (3H, m), 1.61(2H, hex, J 7.3 Hz), 0.95 (3H, t, J 7.3 Hz); m/z (EI⁺, 160V) 506 and508.

EXAMPLE 26

[0302]S-3-[4-(3,5-Dichloropyrid-4-ylcarboxamido)-phenyl-2-(2-nitrophenylamino)propanoicacid The title compound was prepared from Intermediate 3 and2-fluoronitrobenzene, followed by hydrolysis: δH (DMSO d₆)10.86 (1H, br.s), 8.76 (2H, s), 8.20 (1H, d, J 7.7 Hz), 8.08 (1H, dd, J 8.6, 1.6 Hz),7.56 (2H, d, J 8.5 Hz), 7.53 (1H, m), 7.16 (2H, d, J 8.5 Hz), 7.04 (1H,d, J 8.2 Hz), 6.74 (1H, t, J 7.5 Hz), 4.79-4.73 (1H, m), 3.26-3.13 (2H,m); m/z (EI⁺, 60V) 476 and 478.

EXAMPLE 27

[0303]S-3-[4-(3,5-Dichloropyrid-4-ylcarboxamido)-phenyl]-2-(pyrimidin-2-ylamino)propanoicAcid

[0304] The title compound was prepared from Intermediate 3 and2-chloropyrimidine, followed by hydrolysis: δH (DMSO d₆) 10.82 (1H, br.s), 8.76 (2H, s), 8.23 (2H, d, J 4.7 Hz), 7.52 (2H, d, J 8.3 Hz), 7.27(2H, d, J 8.3 Hz), 7.12 (1H, d, J 7.5 Hz), 6.57 (1H, t, J 4.7 Hz),4.50-4.40 (1H, m), 3.12 (1H, dd, J 13.8, 4.5 Hz), 3.00 (1H, dd, J 13.8,9.1 Hz); m/z (EI⁺, 60V) 432 and 434.

EXAMPLE 28

[0305]S-3-[4-(3,5-Dichloropyrid-4-ylcarboxamido)-phenyl-2-(6-methylsulphonylpyrimidin-4-ylamino)propanoicAcid

[0306] The title compound was prepared from Intermediate 3 and2,4-di-(methylsulphonyl)-pyrimidine, followed by hydrolysis: δH (DMSOd₆) 8.79 (2H, s), 8.58 (1H, s), 8.47 (1H, d, J 7.8 Hz), 7.57 (2H, d, J8.5 Hz), 7.28 (2H, d, J 8.5 Hz), 7.21 (1H, s), 4.79 (1H, m), 3.20 (3H,s), 3.19 (1H, m), 3.00 (1H, dd, J 13.9, 9.2 Hz); m/z (EI⁺, 70V) 510.

EXAMPLE 29

[0307]S-3-[4-(3.5-Dichloropyrid-4-ylcarboxamido)-phenyl]-2-(2-propylsulphonylpyrimidin-4-ylamino)propanoicAcid

[0308] The title compound was prepared from Intermediate 3 andIntermediate 13, followed by hydrolysis: δH (DMSO d₆) 8.60 (2H, s), 8.10(1H, d, J 6.0 Hz), 7.50 (2H, d, J 8.5 Hz), 7.28 (2H, d, J 8.5 Hz), 6.70(1H, d, J 6.0 Hz), 4.90 (1H, m), 3.30 (4H, m), 3.10 (1H, m), 1.20 (2H,m), 1.00 (3H, t, J 7.1 Hz); m/z (EI⁺, 70V) 538.

EXAMPLE 30

[0309] S-Ethyl3-[4-(3,5-dichloropyrid-4-ylcarboxamido)-phenyl]-2-(4-methoxy-6-dimethylamino-1,3,5-triazin-2-ylamino)propionate

[0310] To a solution of Intermediate 10 (0.26 g, 0.50 mmol) in dry THF(5 ml) under nitrogen was added dimethylamine (941 mg, 0.5 mmol) andDIPEA (0,17 ml). The solution was stirred at room temperature for 4.5 hthen the solvent was removed in vacuo and DCM (10 ml) was added. Theorganic layer was washed with aqueous sodium bicarbonate and water,dried (MgSO₄) and the solvent removed in vacuo. Flash chromatography(silica; EtOAc/Hexane 1:1) gave the title compound as a froth (0.16 g,59%): δH (CDCl₃) 8.55 (2H, s), 7.75 (1H, br. s), 7.54 (2H, d, J 8.4 Hz),7.18 (2H, d, J 8.4 Hz), 5.40 (1H, m), 4.90 (1H, m), 4.17 (2H, d, J 7.2Hz), 3.84 (3H, s), 3.28-3.10 (2H, m), 3.11 (6H, s), 1.16 (3H, t, J 7.2Hz); m/z (EI⁺, 70V) 534.

EXAMPLE 31

[0311]S-3-[4-(3.5-Dichloropyrid-4-ylcarboxamido)-phenyl]-2-(4-methoxy-6-dimethylamino-1,3,5-triazin-2-ylamino)propanoicAcid

[0312] The title compound was prepared from the compound of Example 30by hydrolysis in a similar manner to Example 2: δH (DMSO d₆) 10.83 (1H,s), 8.77 (2H, s), 7.53 (2H, d, J 8.0 Hz), 7.38 (1H, m), 7.28 (2H, d, J7.9 Hz), 4.72 (1H, m), 3.72 (3H, d, J 4.2 Hz), 3.00 (8H, d, J 4.5 Hz);m/z (EI⁺, 60V) 506.

[0313] In a similar manner were prepared the following compounds ofExamples 32-49

EXAMPLE 32

[0314]S-3-[4-(3.5-Dichloropyrid-4-ylcarboxamido)-phenyl]-2-(4-methoxy-6-diethylamino-1,3,5-triazin-2-ylaminopropanoic Acid

[0315] Prepared from Intermediate 10 and diethylamine, followed byhydrolysis: δH (DMSO d₆, 390K) 10.39 (1H, br. s), 8.65 (2H, s), 7.50(2H, d, J 8.3 Hz), 7.25 (2H, d, J 8.3 Hz), 6.41 (1H, br. m), 4.55 (1H,br. m), 3.54 (4H, dd, J 6.9 Hz), 3.39 (3H, s), 3.20-3.00 (2H, m), 1.11(6H, t, J 6.9 Hz); m/z (EI⁺, 60V) 534.

EXAMPLE 33

[0316]S-3-[4-(3,5-Dichloropyrid-4-ylcarboxamido)-phenyl]-2-(4-methoxy-6-morpholino-1,3,5-triazin-2-ylamino)propanoicAcid

[0317] Prepared from Intermediate 10 and morpholine, followed byhydrolysis: δH (DMSO d₆, 365K) 10.49 (1H, br. s), 8.69 (2H, s), 7.53(2H, d, J 8.1 Hz), 7.25 (2H, d, J 8.4 Hz), 6.87 (1H, br. s), 4.62 (1H,m), 3.78 (3H, s), 3.70-3.55 (8H, m), 3.20-3.00 (2H, m); m/z (EI⁺, 70V)548.

EXAMPLE 34

[0318]S-3-[4-(3.5-Dichloropyrid-4-ylcarboxamido)-phenyl]-2-(4-methoxy-6-propyloxy-1,3,5-triazin-2-ylamino)propanoicAcid

[0319] Prepared from Intermediate 10 and sodium n-propoxide, followed byhydrolysis: δH (DMSO d₆, 390K) 8.69 (2H, s), 7.53 (2H, d, J 8.4 Hz),7.50 (1H, br. m), 7.27 (2H, d, J 8.3 Hz), 4.66 (1H, m), 4.20 (2H, t, J6.6 Hz), 3.82 (3H, s), 3.25-3.00 (2H, m), 1.68 (2H, m, J 6.8 Hz), 0.93(3H, t, J 7.4 Hz); m/z (EI⁺, 60V) 521.

EXAMPLE 35

[0320]S-3-[4-(3.5-Dichloropyrid-4-ylcarboxamido)-phenyl]-2-(4-methoxy-6-phenoxy-1.3.5-triazin-2-ylamino)propanoicAcid

[0321] Prepared from Intermediate 10 and sodium phenoxide, followed byhydrolysis: δH (DMSO d₆) 10.84 (1H, s), 8.77 (2H, s), 8.25 (1H, m), 7.53(2H, d, J 8.4 Hz), 7.40-7.10 (7H, m), 4.52 (1H, m), 4.41 (1H, m), 3.76(3H, s), 3.10-2.80 (2H, m); m/z (EI⁺, 60V) 555.

EXAMPLE 36

[0322]S-3-[4-(3,5-Dichloropyrid-4-ylcarboxamido)-phenyl]-2-(4-methoxy-6-n-propylamino-1,3,5-triazin-2-ylamino)propanoicAcid

[0323] Prepared from Intermediate 10 and n-propylamine, followed byhydrolysis: δH (DMSO d₆, 390K) 10.38 (1H, br. s); 8.67 (2H, s), 7.51(2H, d, J 8.4 Hz), 7.25 (2H, d, J 8.4 Hz), 6.60 (1H, m), 6.44 (1H, m),4.68 (1H, m), 3.77 (3H, s), 3.25-3.00 (4H, m), 1.53 (2H, q, J 14.3, 7.2Hz), 0.88 (3H, t, J 7.4 Hz); m/z (EI⁺, 60V) 520.

EXAMPLE 37

[0324]S-3-[4-(3,5-Dichloropyrid-4-ylcarboxamido)-phenyl]-2-[4-methoxy-6-(2-hydroxyethylamino)-1,3,5-triazin-2-ylamino]propanoicAcid

[0325] Prepared from Intermediate 10 and 2-hydroxyethylamine, followedby hydrolysis: δH (DMSO d₆, 350K) 10.57 (1H, s), 8.72 (2H, s), 7.54 (2H,d, J 8.2 Hz), 7.27 (2H, d, J 8.3 Hz), 6.78-6.68 (1H, m), 4.62 (1H, m),3.77 (3H, s), 3.50 (2H, d. J 6.0 Hz), 3.35 (2H, d, J 5.65 Hz), 3.17-3.02(2H, m); m/z (EI⁺, 60V) 522.

EXAMPLE 38

[0326]S-3-[4-(3,5-Dichloropyrid-4-ylcarboxamido)-phenyl]-2-(4-methoxy-6-(4-carboxylpiperidinyl)-1,3,5-triazin-2-ylamino)propanoicAcid

[0327] Prepared from Intermediate 10 and ethyl piperidine-4-carboxylate,followed by hydrolysis: δH (DMSO d₆, 390K) 10.83 (1H, s), 8.76 (1H, s),7.53 (2H, d, J 8.3 Hz), 7.45 (1H, m), 7.27 (2H, d, J 8.4 Hz), 4.55-4.30(2H, m), 3.72 (3H, s), 3.10-2.80 (2H, m), 1.90-1.75 (2H, m), 1.50-1.30(2H, m); m/z (EI⁺, 70V) 590.

EXAMPLE 39

[0328]S-3-[4-(3.5-Dichloropyrid-4-ylcarboxamido)-phenyl]-2-(4-methoxy-6-piperazinyl-1.3.5-triazin-2-ylamino)propanoicAcid

[0329] Prepared from Intermediate 10 and N-BOC piperazine, followed byhydrolysis and BOC deprotection: δH (DMSO d₆) 10.58 (1H, s), 8.72 (3H,s), 7.53 (2H, d, J 8.5 Hz), 7.24 (2H, d, J 8.5 Hz), 6.86 (1H, m), 4.56(1H, m), 3.78 (3H, s), 3.64 (4H, t, J 5.0 Hz), 3.17-3.00 (2H, m), 2.75(4H, t, J 5.0 Hz); m/z (EI⁺, 60V) 547.

EXAMPLE 40

[0330]S-3-[4-(3,5-Dichloropyrid-4-ylcarboxamido)-phenyl]-2-(4-methoxy-6-(N′-t-butyloxycarbonylpiperazinyl)-1,3,5-triazin-2-ylamino)propanoicAcid

[0331] Prepared from Intermediate 10 and N-BOC piperazine, followed byhydrolysis: δH (DMSO d₆, 390K) 10.34 (1H, s), 8.67 (2H, s), 7.53 (2H, d,J 7.0 Hz), 7.52 (1H, m), 7.27 (2H, d, J 8.4 Hz), 6.65 (1H, d, J 7.6 Hz),4.70 (1H, m), 3.81 (3H, s), 3.70 (4H, m), 3.40 (4H, m), 3.30-3.10 (2H,m), 1.46 (9H, s); m/z (EI⁺, 70V) 647.

EXAMPLE 41

[0332]S-3-[4-(3.5-Dichloropyrid-4-ylcarboxamido)phenyl]-2-(6-methyl-2-propylsulphonylpyrimidin-4-ylamino)propanoicAcid

[0333] Prepared from Intermediate 3 and6-methyl-2,4-di-(n-propylsulphonyl)-pyrimidine, followed by hydrolysis:δH (DMSO d₆) 10.83 (1H, s), 8.77 (2H, s), 8.27 (1H, d, J 8.0 Hz), 7.54(2H, d, J 8.3 Hz), 7.25 (2H, d, J 8.2 Hz), 6.58 (1H, s), 4.66 (1H, m),3.44-2.90 (4H, m), 2.28 (3H, s), 1.67-1.59 (2H, m), 0.96 (3H, t, J 7.4Hz); m/z (EI⁺, 70V) 552.

EXAMPLE 42

[0334]S-3-[4-(3.5-Dichloropyrid-4-ylcarboxamido)-phenyl]-2-(6-benzylsulphonylpyrimidin-4-ylamino)propanoicAcid

[0335] Prepared from Intermediate 3 and4,6-di-(benzylsulphonyl)pyrimidine, followed by hydrolysis: δH (DMSO d₆)10.85 (1H, s), 8.77 (2H, s), 8.62 (1H, s), 8.35 (1H, d, J 7.4 Hz), 7.54(2H, d, J 8.3 Hz), 7.30-7.19 (7H, m), 7.02 (1H, s), 4.71 (1H, m),3.29-2.97 (2H, m), 1.89 (2H, s); m/z (EI⁺, 70V) 586.

EXAMPLE 43

[0336]S-3-[4-(3.5-Dichloropyrid-4-ylcarboxamido)-phenyl]-2-(6-carboxy-2-propylsulphonylpyrimidin-4-ylamino)propanoicAcid

[0337] Prepared from Intermediate 3 and methyl2,6-di-(n-propylsulphonyl) pyrimidine-4-carboxylate, followed byhydrolysis: δH (DMSO d₆) 10.85 (1H, s), 8.76 (1H, s), 8.76 (2H, s), 7.56(2H, d, J 8.5 Hz), 7.35 (1H, s), 7.26 (2H, d, J 8.5 Hz), 4.74 (1H, m),3.74-2.98 (4H, m), 1.70-1.62 (2H, q, J 7.5 Hz), 0.97 (3H, t, J 7.4 Hz);m/z (EI⁺, 70V) 582.

EXAMPLE 44

[0338]S-3-[(4-(3,5-Dichloropyrid-4-ylcarboxamido)-phenyl]-2-(6-methyl-4-(propylaminocarbonyl)-pyrimidin-2-ylamino)propanoicAcid

[0339] Prepared from Intermediate 3 and2-chloro-4-methyl-6-(n-propylamino carbonyl) pyrimidine, followed byhydrolysis: δH (DMSO d₆) 10.82 (1H, s), 8.76 (2H, s), 8.32 (1H, br. s),7.53 (2H, d, J 8.5 Hz), 7.31 (2H, d, J 8.2 Hz), 7.00 (1H, s), 4.75 (1H,m), 3.30-3.10 (4H, m), 2.30 (3H, s), 1.54-1.47 (2H, q, J 14.6, 7.4 Hz),0.87 (3H, t, J 7.3 Hz); m/z (EI⁺, 70V) 531.

EXAMPLE 45

[0340]S-3-[4-(3,5-Dichloropyrid-4-ylcarboxamido)-phenyl]-2-[6-methyl-4-(diethylaminocarbonyl)-pyrimidin-2-ylamino]propanoicAcid

[0341] Prepared from Intermediate 3 and2-chloro-4-methyl-6-(diethylamino-carbonyl) pyrimidine, followed byhydrolysis: δH (DMSO d₆) 10.34 (1H, s), 8.67 (1H, s), 7.51 (2H, d, J 6.3Hz), 7.27 (2H, d, J 8.3 Hz), 6.54 (1H and 1H, together 2H, s), 4.75 (1H,m), 3.35 (4H, m), 3.23-3.07 (2H, m), 2.30 (3H, s), 1.13 (6H, m); m/z(EI⁺, 70V) 545.

EXAMPLE 46

[0342]S-3-[4-(3.5-Dichloropyrid-4-ylcarboxamido)-phenyl]-2-(6-carboxy-2-iso-butylsulphonylpyrimidin-4-ylamino)propanoicAcid

[0343] Prepared from Intermediate 3 and methyl2,6-di-(iso-butylsulphonyl) pyrimidine-4-carboxylate, followed byhydrolysis: δH (DMSO d₆) 10.84 (1H, s), 8.76 (2H, s), 7.55 (2H, d, J 8.5Hz), 7.35 (1H, s), 7.26 (2H, d,J 8.5 Hz), 4.75 (1H, m), 3.39-3.02 (4H,m), 2.14-2.07 (1H, m), 0.98 (6H, d, J 3.3 Hz); m/z (EI⁺, 70V) 596.

EXAMPLE 47

[0344]S-3-[4-(3.5-Dichloropyrid-4-ylcarboxamido)-phenyl]-2-(6-carboxy-2-hexylsulphonylpyrimidin-4-ylamino)propanoicAcid

[0345] Prepared from Intermediate 3 and methyl 2,6-di-(n-hexylsulphonyl)pyrimidine-4-carboxylate, followed by hydrolysis: δH (DMSO d₆) 10.84(1H, s), 8.78 (2H, s), 7.54 (2H, d, J 8.4 Hz), 7.36 (1H, s), 7.25 (2H,d, J 8.5 Hz), 4.77-4.71 (1H, m), 3.40-3.00 (4H, m), 1.65 (2H, m), 1.36(2H, m), 1.24 (2H, t, J 3.3 Hz), 0.82 (3H, t, J 6.9 Hz); m/z (EI⁺, 70V)624.

EXAMPLE 48

[0346]S-3-[4-(3,5-Dichloropyrid-4-ylcarboxamido)-phenyl]-2-(4,6-dimethoxy-1,3,5-triazin-2-ylamino)propanoicAcid

[0347] The title compound was prepared from Intermediate 7 and2-chloro-4,6-dimethoxy-1,3,5-triazine, followed by hydrolysis: δH (DMSOd₆) 8.70 (2H, s), 8.10 (1H, d, J 8.0 Hz), 7.24 (2H, d, J 8.3 Hz), 6.95(2H, d, J 8.3 Hz), 5.18 (2H, s), 4.52 (1H, m), 3.81 (3H, s), 3.80(3H,s), 3.15-2.90 (2H, m); m/z (EI⁺, 60V) 480.

EXAMPLE 49

[0348]S-3-[4-(3,5-Dichloropyrid-4-ylcarboxamido)-phenyl]-2-(4,6-propyloxy-1,3,5-triazin-2-ylamino)propanoicAcid

[0349] Prepared from Intermediate 3 and2-chloro-4,6-di-n-propoxy-1,3,5-triazine, followed by hydrolysis: δH(DMSO d₆) 10.84 (1H, br. s), 8.77 (2H, s), 8.00 (1H, d, J 7.8 Hz), 7.54(2H, d, J 8.4 Hz)., 7.30 (2H, d, J 8.4 Hz), 4.52 (1H, m), 3.15-2.80 (2H,m), 1.64 (4H, m), 0.89 (6H, m); m/z (EI⁺, 60V) 549.

EXAMPLE 50

[0350] S-Methyl3-[4-(3.5-dichloropyrid-4-ylcarboxamido)-phenyl]-2-(N-methyl-4.6-dimethoxy-1.3.5-triazin-2-ylamino)propionate

[0351] The title compound (350 mg, 80%) was prepared in an analogousmanner to the compound of Example 1 starting from S-Methyl3-[4-(3,5-dichloropyrid-4-ylcarboxamido)-phenyl]-2-(N-methylamino)propionatehydrochloride (500mg 1.19 mmol): δH (CDCl₃) 8.55 (2H, s), 7.80 (1H, s),7.50 (2H, d, J 8.0 Hz), 7.20 (2H, d, J 8.0 Hz), 5.40 (1H, m), 4.00 (3H,s), 3.95 (3H, s), 3.75 (3H, s), 3.50 (2H, m), 3.10 (3H, s); m/z (EI⁺,70V) 521.

EXAMPLE 51

[0352]S-3-[4-(3.5-Dichloropyrid-4-ylcarboxamido)-phenyl]-2-(N-methyl-4,6-dimethoxy-1,3,5-triazin-2-ylamino)propanoicAcid

[0353] The title compound was prepared from the compound of Example 50by the method of Example 2: δH (DMSO d₆) 10.81 (s, 1H), 8.77 (2H, s),7.51 (2H, d, J 8.5 Hz), 7.23 (2H, d, 18.5 Hz), 5.34 (1H, m), 3.81 (3H,s), 3.80 (3H, s), 3.22 (2H, m), 2.92 (3H, s); m/z (EI⁺, 70V) 507.

EXAMPLE 52

[0354]R-3-[4-(3.5-Dichloropyrid-4-ylcarboxamido)-phenyl]-2-(4.6-dimethoxy-1,3,5-triazin-2-ylamino)propanoicacid

[0355] The title compound was prepared fromR-ethyl-3-[4-(3,5-dichloropyrid-4-ylcarboxamido)phenyl-2-aminopropionatehydrochloride in an analogous fashion to the compounds of Examples 1 and2: δH (DMSO d₆) 10.84 (s, 1H), 8.72 (2H, s), 8.15 (1H, d, J 7.8 Hz),7.55 (2H, d, J 8.4 Hz), 7.30 (2H, d, J 8.4 Hz), 4.55 (1H, m), 3.80 (3H,s), 3.78 (3H, s), 3.12 (1H, dd, J 13.8, 4.5 Hz), 3.01 (1H, dd, J 13.8,10.3 Hz); m/z (EI⁺, 70V) 493.

EXAMPLE 53

[0356] S-Ethyl3-[4-N-methyl-(3,5-dichloropyrid-4-ylcarboxamido)-phenyl]-2-(N-methyl-4,6-dimethoxy-1,3,5-triazin-2-ylamino)propionate

[0357] To a solution of the ethyl ester analogue of the compound ofExample 50 (310 mg, 0.59 mmol) in DMF (10 ml) was added cesium carbonate(388 mg, 1.18 mmol) and iodomethane (390 μl, 590 mmol) and the mixturewas stirred at room temperature for 16 h. The reaction was concentratedin vacuo and extracted with ethyl acetate (50 ml). The organics werewashed with water (2×50 ml), dried (Na₂SO₄) and evaporated. The residuewas chromatographed (silica; EtOAc/Hexane 1:1) to give the titlecompound as a white solid (100 mg, 31%): δH (CDCl₃) 8.35 (1H, d), 7.20(2H, d), 7.00 (2H, d), 5.10 (1H, m), 4.10 (2H, m), 4.00 (3H, s), 3.90(3H, s), 3.49 (3H, s), 3.40 (1H, m), 3.30 (1H, m), 2.80 (3H, m), 1.20(3H, m); m/z (EI⁺, 70V) 549.

EXAMPLE 54

[0358]S-3-[4-N-Methyl-(3.5-dichloropyrid-4-ylcarboxamido)-phenyl]-2-(N-methyl-4,6-dimethoxy-1,3,5-triazin-2-ylamino)propanoicacid

[0359] The title compound was prepared from the compound of Example 53in an analogous manner to Example 2: δH (DMSO d₆) 8.37, (1H, s), 8.32(1H, s), 7.18 (2H, d, J 8.4 Hz), 7.11 (2H, d, J 8.4 Hz), 5.24 (1H, dd, J11.0, 5.3 Hz), 3.85 (6H, s), 3.36 (3H, s), 3.19 (2H, m), 2.77 (3H, s);m/z (EI⁺J 70V) 521.

EXAMPLE 55

[0360]S-Ethyl[4-(3.5-dichloropyrid-4-ylcarboxamido)phenyl]-2-[(6-chloropyridazin-3-yl)amino]-propionate

[0361] A solution of the compound of Intermediate 3 (420 mg, 1 mmol) inCH₃CN (2 ml) was treated with DIPEA (0.36 ml, 2.1 mmol) and3,6dichloropyridazine (164 mg, 1.1 mmol) and heated to refluxtemperature for 36 h. The solvent was removed in vacuo, the residuere-dissolved in EtOH (2.5 ml) and a further portion of pyridazine (82mg, 0.55 mmol) and DIPEA (0.18 ml, 1.1 mmol) were added. The resultingmixture was heated to reflux for 48 h, the solvent was removed in vacuoand the residue was dissolved in EtOAc (20 ml) and washed with 10%citric acid (2×10 ml), NaHCO₃ (2×10 ml) and brine (10 ml), dried (MgSO₄)and the solvent removed in vacuo. The product was purified bychromatography (silica 2-5% MeOH/DCM) to give the title compound as awhite solid (80 mg, 16%): δH (DMSO d₆) 10.85 (1H, s), 8.77 (2H, s), 7.56(2H, d, J 8.5 Hz), 7.50 (1H, d, J 7.7 Hz), 7.39 (1H, d, J 9.3 Hz), 7.26(2H, d, J 8.5 Hz), 7.02 (1H, d, J 9.3 Hz), 4.20 (1H, m), 4.06 (2H, q, J7.1 Hz), 3.10 (2H, m), 1.12 (3H, t, J 7.1 Hz); m/z (EI⁺, 60V) 494.

EXAMPLE 56

[0362]S-[4-(3,5-Dichloropyrid-4-ylcarboxamido)phenyl]-2-[(6-chloropyridazin-3-yl)amino]propanoicAcid

[0363] The title compound (50 mg, 79%) was prepared from the compound ofExample 55 by hydrolysis in a similar manner to Example 2 (67 mg, 0.14mmol): δH (DMSO d₆) 10.84 (1H, s), 8.77 (2H, s), 7.55 (2H, d, J 8.5 Hz),7.37 (1H, d, J 9.3 Hz), 7.35 (1H, m), 7.26 (2H, d, J 8.5 Hz), 7.01 (1H,d, J 9.3 Hz), 4.67 (1H, m), 3.17 (1H, dd, J 18.8, 5.0 Hz), 2.96 (1H, dd,J 22.6, 8.9 Hz); m/z (EI⁺, 60V) 466.

EXAMPLE 57

[0364]S-Ethyl-3-(4-nitrophenyl)-2-[(4,6-dimethoxy-1.3.5-triazin-2-yl)amino]propionate

[0365] 2-Chloro-4,6-dimethoxy-1,3,5-triazine (8.05 g, 45.8 mmol) wasadded to a solution of (S)-4-nitrophenylalanine ethyl esterhydrochloride (5.0 g, 38.2 mmol) and DIPEA (13.6 ml, 78.3 mmol) inacetonitrile (80 ml) and the reaction was stirred at room temperaturefor 16 h, concentrated in vacuo and the residue partitioned betweenEtOAc (100 ml) and NaHCO₃ solution (100 ml). The organic layer waswashed with 10% citric acid solution 100 ml), NaHCO₃ solution (100 ml)and water (100 ml), dried (MgSO₄) and concentrated in vacuo. The crudeproduct was purified by chromatography (silica; EtOAc/Hexane 1:1) togive the title compound (6.66 g, 97%): δH (CDCl₃) 8.10 (2H, d, J 9.0Hz), 7.30 (2H, d, J 9.0 Hz), 6.10 (1H, m), 5.0 (1H, m), 4.1 (2H, q, J7.1 Hz), 3.92 (3H, s), 3.90 (3H, s), 3.30 (2H, m), 1.25 (3H, t, J 7.1Hz); m/z (EI⁺, 70V) 378.

EXAMPLE 58

[0366]S-Ethyl-3-(4-aminophenyl)-2-[(4,6-dimethoxy-1,3,5-triazin-2-ylamino]propionate

[0367] Palladium (10% on charcoal) (660 mg) was added to a solution ofthe compound of Example 57 (6.66 g, 24.3 mmol) in EtOH (100 ml) andstirred under an atmosphere of hydrogen for 16 h. The catalyst wasremoved by filtration and the solution concentrated in vacuo to give thetitle compound as a pink solid (5.26 g, 86%) which was used withoutfurther purification: δH (CDCl₃) 6.90 (2H, d), 6.60 (2H, d), 5.75 (1H,d), 4.90 (1H, m), 4.10 (2H, q), 3.95 (3H, s), 3.90 (3H, s), 3.10 (2H,m), 1.30 (3H, t); m/z (ES⁺, 70V) 348.

EXAMPLE 59

[0368]S-Ethyl-3-[4-(2.6-dichlorophenylcarboxamido)phenyl]-2-[(4.6-dimethoxy-1,3,5-triazin-2-yl)amino]propionate

[0369] 2,6-Dichlorobenzoyl chloride (0.22 ml, 1.5 mmol) was added to asolution of the compound of Example 58 (0.50 g, 1.4 mmol) and NMM (0.17ml, 1.5 mmol) in DCM (10 ml). The reaction was stirred at roomtemperature for 72 h, then partitioned between DCM (50 ml) and NaHCO₃solution (50 ml). The organic layer was washed with 10% citric acidsolution (50 ml), NaHCO₃ solution (50 ml) and water (50 ml), dried(MgSO₄) and concentrated in vacuo to give the title compound as a pinksolid (0.61 g, 82%) which was used without further purification: δH(CDCl₃) 7.60 (2H, d), 7.30 (3H, m), 7.10 (2H, d), 5.90 (1H, d), 4.90(1H, m), 4.20 (2H, m), 3.90 (3H, s), 3.89 (3H, s), 3.20 (2H, m), 1.25(3H, m); m/z (EI⁺, 70V) 520.

EXAMPLE 60

[0370]S-3-[4-(2,6-Dichlorophenylcarboxamido)phenyl]-2-[(4,6-dimethoxy-1,3,5-triazin-2-yl)amino]propanoicAcid

[0371] The title compound was prepared by hydrolysis in a similar mannerto Example 2 from the compound of Example 59: δH (DMSO d₆) 10.70 (1H,s), 8.15 (2H, d), 7.50 (6H, m), 7.25 (2H, d), 4.50 (1H, m), 3.75 (6H,m), 3.00 (2H, m); m/z (EI⁺, 60V) 492.

EXAMPLE 61

[0372]S-Ethyl-3-[4-(2-fluoro-6-trifluoromethylphenylcarboxamido)phenyl]-2-[(4,6-dimethoxy-1,3,5-triazin-2-yl)amino]propionate

[0373] The title compound was prepared in an analogous manner to thecompound of Example 59 using 2-fluoro-6-trifluoromethylbenzoyl chloride:δH (CDCl₃) 7.6 (5H, m), 7.40 (1H, m), 7.10 (2H, d, J 8.0 Hz), 5.90 (1H,d, J 6.0 Hz), 5.0 (1H, m), 4.2 (2H, q), 3.90 (2×3H, s), 3.20 (2H, m),1.25 (3H, t); m/z (EI⁺, 70V) 538.

EXAMPLE 62

[0374]S-3-[4-(2-Fluoro-6-trifluoromethylphenylcarboxamido)phenyl]-2-[(4,6-dimethoxy-1,3,5-triazin-2-yl)amino]propanoicAcid

[0375] The title compound was prepared from the compound of Example 61by hydrolysis in a similar manner to Example 2: δH (DMSO d₆) 8.10 (2H,m), 7.80 (3H, m), 7.50 (2H, m), 7.30 (2H, m), 4.50 (1H, m), 3.70 (6H,s), 3.00 (2H, m); m/z (EI⁺, 70V) 510.

EXAMPLE 63

[0376]S-Ethyl-3-[4-(4,6-dimethoxy-1,3,5-triazin-2-yl)aminophenyl]-2-[(4.6-dimethoxy-1,3,5-triazin-2-yl)amino]propionate

[0377] 2-Chloro-4,6-dimethoxy-1,3,5-triazine (0.30 g, 1.7 mmol) wasadded to a solution of the compound of Example 58 (0.50 g, 1.4 mmol) andDIPEA (0.60 ml, 3.2 mmol) in CH₃CN (10 ml). The reaction was stirred atroom temperature for 72 h, then concentrated in vacuo, partitionedbetween EtOAc (50 ml) and NaHCO₃ solution (50 ml). The organic layer waswashed with 10% citric acid solution (50 ml), NaHCO₃ solution (50 ml)and water (50 ml), dried (MgSO₄) and concentrated in vacuo to give thetitle compound as an off white solid (0.23 g, 32%) which was usedwithout further purification: δH (CDCl₃) 7.5 (2H, d, J 9.0 Hz), 7.10(2H, d, J 9.0 Hz), 6.05 (1H, d, J 6.0 Hz), 5.0 (1H, m), 4.15 (2H, q),4.05 (6H, s), 3.95 (6H, s), 3.20 (2H, m). 1.25 (3H, m); m/z (EI⁺, 70V)487.

EXAMPLE 64

[0378]S-3-[4-(4,6-Dimethoxy-1,3,5-triazin-2-yl)aminophenyl]-2-[(4,6-diemthoxy-1.3.5-triazin-2-yl)amino]propanoicAcid

[0379] The title compound was prepared from the compound of Example 63by hydrolysis in a similar manner to Example 2: δH (DMSO d₆) 10.00 (1H,s), 8.20 (2H, d), 7.55 (2H, d), 7.20 (2H, d), 4.55 (1H, m), 3.90 (6H,s), 3.80 (6H, s), 3.00 (2H, m); m/z (EI⁺, 70V) 459.

EXAMPLE 65

[0380] S-Ethyl3-[4-(4.6-dimethoxy-1,3,5-triazin-2-yl)phenoxyl]-2-[(4.6-dimethoxy-1.3.5-triazin-2-yl)amino]propionate

[0381] A solution of Intermediate 11 (0.50 g, 1.43 mmol) in DMF (10 ml)was treated with caesium carbonate (0.94 g, 2.86 mmol) and stirred atroom temperature for 15 min. 2-Chloro-4,6-dimethoxy-1,3,5-triazine (0.25g, 1.43 mmol) was added and the reaction stirred for 16 h thenconcentrated in vacuo, and partitioned between EtOAc (50 ml) and water(50 ml). The organic layer was separated, dried (MgSO₄) and concentratedin vacuo to give the title compound as an off-white solid (0.47 g, 67%):δH (DMSO d₆) 7.25 (2H, d, J 7.0 Hz), 7.20 (2H, d, J 7.0 Hz), 5.90 (1H,d), 5.00 (1H, m), 4.20 (2H, m), 4.00 (12H, s), 3.20 (2H, m), 1.20 (3H,t, J 7.1 Hz); m/z (EI⁺, 70V) 488.

EXAMPLE 66

[0382]S-3-[4-(4,6-Dimethoxy-1,3,5-triazin-2-yl)phenoxy]-2-[(4,6-dimethoxy-1,3,5-triazin-2-yl)amino]propanoicAcid

[0383] The title compound was prepared from the compound of Example 65,by hydrolysis in a similar manner to Example 2: δH (DMSO d₆) 8.00 (1H,s), 7.35 (2H, d, J 8.0 Hz), 7.10 (2H, d, J 8.0 Hz), 4.50 (1H, m), 3.85(6H, s), 3.79 (6H, s), 3.77 (6H, s), 3.20 (2H, m); m/z (EI⁺, 70V) 460.

EXAMPLE 67

[0384] S-Ethyl3-[(4-(2.6-dichlorobenzyl)phenoxy]-2-[(4.6-dimethoxy-1,3,5-triazin-2-yl)amino]propionate

[0385] A solution of Intermediate 11 (0.50 g, 1.43 mmol) in DMF (10 ml)was treated with caesium carbonate (0.948, 2.86 mmol) and stirred atroom temperature for 15 min. 2,6-Dichlorobenzyl bromide (0.38 g, 1.58mmol) was added and the reaction stirred for 16 h then concentrated invacuo, and partitioned between EtOAc (50 ml) and water (50 ml). Theorganic layer was separated, washed with water (2×50 ml), dried (MgSO₄)and concentrated in vacuo. The residue was purified by chromatography(silica; EtOAc/Hexane 1:1) to give the title compound as an oil (0.26 g,36%): δH (DMSO d₆) 7.45 (1H, m), 7.40 (1H, m), 7.35 (1H, m), 7.10 (2H,d), 6.90 (2H, d), 5.8 (1H, d), 5.25 (2H, s), 4.10 (2H, m), 3.90 (6H, s),3.10 (2H, m), 1.3 (3H, m); m/z (EI⁺, 70V) 507.

EXAMPLE 68

[0386]S-3-[4-(2,6-Dichlorobenzyl)phenoxy]-2-[(4.6-dimethoxy-1,3,5-triazin-2-yl)amino]propanoicAcid

[0387] The title compound was prepared from the compound of Example 67,by hydrolysis in a similar manner to Example 2: δH (DMSO d₆) 8.10 (1H,d), 7.50 (2H, m), 7.45 (1H, m), 7.25 (2H, d, J 8.0 Hz), 6.95 (2H, d, J8.0 Hz), 5.15 (2H, m), 4.50 (1H, m), 3.80 (3H, s), 3.75 (3H, s), 3.00(2H, m); m/z (EI⁺, 70V) 479.

EXAMPLE 69

[0388]S-3-[4-(3.5-Dichloropyrid-4-ylcarboxamido)phenyl]-2-[3-(propylsulphonyl)pyrazin-2-ylamino]propanoicAcid

[0389] The title compound was prepared in an analogous manner to thecompound of Example 1 starting from Intermediate 3 and Intermediate 12,followed by hydrolysis: δH (DMSO d₆) 10.86 (1H, s), 8.77 (2H, s), 8.40(1H, d, J 2.3 Hz), 7.99 (1H, d, J 2.3 Hz), 7.55 (2H, d, J 8.5 Hz), 7.37(1H, d, J 7.0 Hz), 7.18 (2H, d, J 8.5 Hz), 4.80 (1H, br. q), 3.38-3.22(3H, m), 3.10 (1H, dd, J 13.9, 7.0 Hz), 1.55-1.46 (2H, m), 0.88 (3H, t,J 7.4 Hz); m/z (EI⁺, 70V) 538.

EXAMPLE 70

[0390]S-3-[4-(3.5-Dichloropyrid-4-ylcarboxamido)phenyl]-2-[3-chloropyrazin-2-ylamino]propanoicAcid

[0391] The title compound was prepared in an analogous manner to thecompound of Example 5 starting from Intermediate 3 and2,3dichloropyrazine, followed by hydrolysis: δH (DMSO d₆) 12.81 (1H, br.s), 10.83 (1H, s), 8.77 (2H, s), 7.99 (1H, d, 12.7 Hz), 7.61 (1H, d, J2.7 Hz), 7.54 (2H, d, J 8.5 Hz), 7.28 (2H, d, J 8.5 Hz), 6.87 (1H, d, J7.9 Hz), 4.68-4.61 (1H, m), 3.22 (2H, m); m/z (EI⁺, 70V) 466.

EXAMPLE 71

[0392]S-3-[4-(3,5-Dichloropyrid-4-ylcarboxamido)phenyl]-2-[6-chloropyrazin-2-ylamino]propanoicAcid

[0393] The title compound was prepared in an analogous manner to thecompound of Example 5 starting from Intermediate 3 and2,6dichloropyrazine, followed by hydrolysis: δH (DMSO d₆) 12.82 (1H, br:s), 10.84 (1H, s), 8.77 (2H, s), 7.97 (1H, s), 7.84 (1H, d, J 8.0 Hz),7.72 (1H, s), 7.54 (2H, d, J 8.5 Hz), 7.27 (2H, d, J 8.5 Hz), 4.51 (1H,ddd, J 8.9, 8.0, 4.9 Hz), 3.15 (1H, dd, J 13.9, 4.4 Hz), 2.96 (1H, dd, J13.9, 9.1 Hz); m/z (EI⁺, 70V) 466.

EXAMPLE 72

[0394] S-Ethyl3-[4-(3,5-Dichloropyrid-4-ylcarboxamido)phenyl]-2-[3-chloroguinoxalin-2-ylamino]propionate

[0395] The title compound was prepared in an analogous manner to thecompound of Example 5 starting from Intermediate 3 and2,3-dichloroquinoxaline. The product contains some ethoxyethylester as aresult of transesterification in the ethoxyethanol used as solvent inthis case: δH (DMSO d₆) 10.38 (1H, s), 8.76 (2H, s), 7.76 (1H, d, J 8.2Hz), 7.65-7.41 (6H, m), 7.32 (2H, d, J 8.4 Hz), 4.82-4.75 (1H, m),4.17-4.06 (2H, m), 3,40-3.20 (2H, m), 1.14 (3H, t, J 7.1 Hz); m/z (ES⁺,70V) 544. For the ethoxyethyl ester: δH (DMSO d₆) 3.47-3.42 (m). 0.97(3H, t, J 7.0 Hz); m/z (EI⁺, 70V) 588.

EXAMPLE 73

[0396]S3-[4-(3,5-Dichloropyrid-4-ylcarboxamido)phenyl]-2-[3-chloroquinoxalin-2-ylamino]propanoic-Acid

[0397] The title compound was prepared from the compound of Example 72by hydrolysis: δH (DMSO d₆) 12.84 (1H, br. s), 10.81 (1H, s), 8.76 (2H,s), 7.76 (1H, d, J 8.2 Hz), 7.63-7.61 (2H, m), 7.54 (1H, d, J 8.5 Hz),7.46-41 (1H, m), 7.33-7.25 (3H, m), 4.86-4.79 (1H, m), 3.30-3.26 (2H,m); m/z (EI⁺, 70V) 516.

EXAMPLE 74

[0398]S-3-[4-(3.5-Dichloropyrid-4-ylcarboxamido)phenyl]-2-[3-phenoxyquinoxalin-2-ylamino]propanoicAcid

[0399] The title compound was prepared in an analogous manner to thecompound of Example 5 starting from Intermediate 3 and Intermediate 14followed by hydrolysis: δH (DMSO d₆) 12.90 (1H, br. s), 10.83 (1H, s),8.76 (2H, s), 7.57-7.23 (14H, m), 4.91-4.84 (1H, m), 3.30 (2H, br. d J6.6 Hz); m/z (EI⁺, 70V) 574.

EXAMPLE 75

[0400] S-Ethyl 3-[4-(3.5-Dichloropyrid-4-ylcarboxamidophenyl]-2-[3-morpolinoquinoxalin-2-ylamino]propionate

[0401] A mixture of the compound of Example 73 (300 mg, 0.55 mmol),morpholine (58 μl, 0.66 mmol) and DIPEA (192 μL, 1.1 mmol) inethoxyethanol (2 ml) was heated at reflux overnight. The solvent wasremoved in vacuo. The residue was dissolved in DCM, washed with dil.HCl, dried (Na₂SO₄) and evaporated in vacuo. Column chromatography(silica; EtOAc/Hexane 6:4) gave the title compound (280 mg) as a brownoil, which contains some of the corresponding ethoxyethyl ester, fromtransesterification: δH (DMSO d₆) 10.84 (1H, s), 8.77 (2H, s), 7.61-7.27(8H, m), 6.70 (1H, d, J 7.8 Hz), 4.75 (1H, m), 4.21-4.07 (2H, m andethoxyethyl ester), 3.86-3.80 (2H, m), 3.71-3.66 (2H, m), 3.50 (m,ethoxyethyl ester), 3.30-(2H, m), 3.12-3.17 (2H, m), 2.97-2.91 (2H; m),1.16 (t, J 7.1 Hz) and 1.00 (t, J 7.0 Hz) together (3H); m/z (EI⁺, 70V)595, 639 (ethoxyethyl ester).

EXAMPLE 76

[0402]S-3-[4-(3,5-Dichloropyrid-4-ylcarboxamido)phenyl]-2-[3-morpolinoguinoxalin-2-ylamino]propanoicAcid

[0403] The title compound was prepared by starting from the compound ofExample 75 followed by hydrolysis: δH (DMSO d₆) 10.83 (1H, s), 8.76 (2H,s), 7.61-7.26 (8H, m), 6.55 (1H, d, J 7.8 Hz), 4.74 (1H, m), 3.84-3.79(2H, m), 3.69-3.64 (2H, m), 3.30-3.20 (2H, m), 3.20-3.10 (2H, m),2.93-2.88 (2H, m); m/z (EI⁺, 70V) 567.

EXAMPLE 77

[0404] Ethyl2-[4-(3,5-dichloropyrid-4-ylcarboxamido)benzyl]-3-[6-(propylsulphonyl)-pyrimidin-4-ylamino]propionate

[0405] A mixture of Intermediate 19 (440 mg, 1.11 mmol) Intermediate 13(271 mg, 0.93 mmol). and DIPEA (193 μl, 1.11 mmol) in CH₃CN (5 ml) wasstirred at room temperature for 2 h. The solvent was removed in vacuoand the residue dissolved in DCM, washed with dil. HCl, dried (Na₂SO₄)and evaporated in vacuo. Column chromatography (silica; MeOH/DCM 5:95)gave the title compound as a colourless oil (400 mg): δH (DMSO d₆) 10.85(1H, s), 8.78 (2H, s). 8.30 (1H, br. t, J 5.7 Hz), 7.55 (2H, d, J 8.5Hz), 7.20 (2H, d,J 8.5 Hz), 7.10 (1H, s), 3.97 (2H, q, J 7.4 Hz), 3.60(2H, br. m), 3.36-3.27 (4H, m), 2.99, (1H, m), 1.58 (2H, sext J 7.5 Hz),1.03 (3H, t, J 7.1 Hz), 0.93 (3H, t, J 7.4 Hz): m/z (EI⁺, 70V) 580.

EXAMPLE 78

[0406]2-[4-(3.5-Dichloropyrid-4-ylcarboxamido)benzyl]-3-[6-(propylsulphonyl)-pyrimidin-4-ylamino]propanoicAcid

[0407] The title compound was prepared by hydrolysis from the compoundof Example 77 in a similar manner to Example 2: δH (DMSO d₆) 12.38 (1H,br. s), 10.85 (1H, s), 8.78 (2H, s), 8.57(1H, s), 8.30 (1H, br, m), 7.55(2H, d, J 8.5 Hz), 7.21 (2H, d, J 8.5 Hz), 7.12 (1H, s), 3.55 (2H, br.m), 3.33-3.29; 4H, m), 2.95-2.83, (1H, m), 1.59 (2H, sext, J 7.6 Hz),0.94 (3H, t, J 7.4 Hz): m/z (EI⁺, 70V) 552.

EXAMPLE 79

[0408] Ethyl3-[4-(3,5-dichloropyrid-4-ylcarboxamido)phenyl]-2-(3-benzyloxybenzeneamino)propionate

[0409] A solution of Intermediate 20 (500 mg, 1.3 mmol),3-benzyloxyaniline (1.1 equiv) and rhodium (II) acetate dimer (5 mol %)in anhydrous toluene (20 ml) were stirred at 80° for 7 h. The mixturewas cooled and the volatiles removed in vacuo. The residue was purifiedby chromatography (silica; 1% MeOH/DCM) to give the title compound (500mg, 70%): δH (CDCl₃) 3.50 (2H, s), 8.06 (1H, br. s), 7.49 (2H, d, J 8.5Hz), 7.43-7.26 (6H, m), 7.14 (2H, d, J 8.5 Hz), 7.05 (1H, t, J 8.5 Hz),6.37 (1H, d, J 7.3 Hz), 6.24 (2H, m), 3.00 (2H, s), 4.40-4.08 (4H, m),3.13 (1H, dd, J 13.4, 7 Hz), 3.02 (1H, dd, J 13.4, 5.9 Hz), 1.20 (3H, t,J 7.2 Hz): m/z (EI⁺, 70V) 564.

EXAMPLE 80

[0410] Ethyl3-[4-(3.5-dichloropyrid-4-ylcarboxamido)phenyl]-2-(3-propylthiobenzeneamino)propionate

[0411] The title compound was prepared by a similar procedure to thecompound of Example 79, starting from 3-propylthioaniline: δH (CDCl₃)8.56 (2H, s), 7.72-7.58 (2H, m), 7.53 (2H, d, J 8.5 Hz), 7.10 (2H, d, J8 AHz), 7.04 (1H, t, J 7.9 Hz), 6.68 (1H, d, J 7.9 Hz), 6.57 (1H, s),6.42 (1H, d), 4.40-4.10 (3H, m), 3.25-3.07 (2H, m), 2.83 (2H, t, J 7.3Hz), 1.63 (2H, m), 1.21 (3H, t, J 6.8 Hz), 1.01 (3H, t, J 7.4 Hz): m/z(EI⁺, 70V) 532.

EXAMPLE 81

[0412] Ethyl3-[4-(3.5-dichloropyrid-4-ylcarboxamido)phenyl]-2-(4-ethoxycarbonylbenzeneamino)Propionate

[0413] The title compound was prepared by a similar procedure to thecompound of Example 79, starting from ethyl 4-aminobenzene carboxylate:δH (CDCl₃) 8.58 (2H, s), 7.85 (2H, d, J 8.8 Hz), 7.56-7.51 (3H, m), 7.15(2H, d, 8.5 Hz), 6.56 (1H, d, J 8.8 Hz), 4.70-4.60 (1H, br. m),4.55-4.45 (1H, br. m), 4.32 (2H, q,j 7.2 Hz), 4.16 (2H, q, J 7.1 Hz),3.30-3.14 (2H, m), 1.33 (3H, t, J 7.2 Hz), 1.23 (3H, t, J 7.1 Hz): m/z(EI⁺, 70V) 530.

EXAMPLE 82

[0414] Ethyl3-[4-(3,5-dichloropyrid-4-ylcarboxamido)phenyl]-2-(3-propylsulphonylbenzeneamino)Propionate

[0415] The title compound was prepared by oxidation of the compound ofExample 80 with mCPBA: δH (CDCl₃) 8.47 (2H, s), 8.36 (1H, br. s), 7.51(2H, d, J 8.5 Hz), 7.30 (1H, t, J 7.9 Hz), 7.12 (2H, d, J 8.4 Hz), 7.01(1H, m), 6.78 (1H, m), 4.61 (1H, br. m), 4.40 (1H, br. m), 4.10 (2H, q,J 5.9 Hz), 3.15 (1H, dd, J 13.9, 5.6 HZ), 3.05 (1H, dd, J 13.9, 6.3 Hz),2.95 (2H, m), 1.61 (2H, m), (3H, t, J 7.2 Hz), 0.94 (3H, t, J 7.4 Hz):m/z (EI⁺, 70V) 564.

EXAMPLE 83

[0416] Ethyl3-[4-(3.5-dichloropyrid-4-ylcarboxamido)phenyl]-2-(3-propylsulphinylbenezeneamino)Propionate The title compound was prepared by oxidation of the compoundof Example 80 with mCPBA: δH (CDCl₃) 9.11 (1H, d, J 8.3 Hz), 8.44 (2H,s), 7.56 (2H, d, J 8.0 Hz), 7.21 (1H, t, J 7.8 Hz), 7.12 (2H, m),6.80-6.64 (3H, m), 4.65-4.35 (2H, br. m), 4.10 (2H, q, J 7.1 Hz),3.20-3.00 (2H, m), 2.70-2.50 (2H, m), 1.80-1.50 (2H, m), (3H, t, J 8.7Hz), 0.99 (3H, t, J 7.5 Hz): m/z (EI⁺, 70V) 548.

EXAMPLE 84

[0417] Ethyl3-[4-(3,5-dichloropyrid-4-ylcarboxamido)phenyl]-3-(4-ethylacetatobenzeneamino)Propionate

[0418] The title compound was prepared by a similar procedure to thecompound of Example 79, starting from ethyl 4-aminobenzene acetate: δH(CDCl₃) 8.57 (2H, s), 7.81 (2H, d, J 8.5 Hz), 7.17 (2H, d, J 8.5 Hz),7.06 (2H, d, J 8.8 Hz), 6.55 (2H, d, J 8.6 Hz), 4.30 (1H, br. m), 4.10(4H, m), 3.48 (2H, s), 3.25-3.00 (2H, m), 1.20 (6H, m): m/z (EI⁺, 70V)544.

EXAMPLE 85

[0419] Ethyl3-[4-(3,5-dichloropyrid-4-ylcarboxamido)phenyl]-2-(3-acetylbenzeneamino)Propionate

[0420] The title compound was prepared by a similar procedure to thecompound of Example 79, starting from 3-amino acetophenone: δH (CDCl₃)8.56 (2H, s), 7.65 (1H, br. m), 7.40-7.10 (5H, m), 6.80 (1H, m),4.50-4.30 (2H, br. m), 4.16 (2H, q, J 7.2 Hz), 3.25-3.10 (2H, m), 2.54(3H, s), 1.22 (3H, t, J 7.2 Hz): m/z (EI⁺, 70V).

EXAMPLE 86

[0421] Ethyl3-[4-(3.5-dichloropyrid-4-ylcarboxamido)phenyl]-2-(2-chloro-pyridine-3-amino)Propionate

[0422] The title compound was prepared by a similar procedure to thecompound of Example 79, starting from 3-amino-2-chloro-pyridine: δH(CDCl₃) 8.56 (2H, s), 7.78 (1H, br. s), 7.70 (1H, d, J 4.7 Hz), 7.56(2H, d, J 8.5 Hz), 7.20 (2H, d, J 8.5 Hz), 7.04 (1H, m), 6.78 (1H, m, J8.0, 1.3 Hz), 4.87 (1H, br. m), 4.40-4.15 (3H, m), 3.18 (1H, dd, J 14.0,5.7 Hz), 3.11 (1H, dd, J 13.7, 6.6 Hz), 1.23 (3H, t, J 7.1 Hz): m/z(EI⁺, 70V) 493.

EXAMPLE 87

[0423] Ethyl3-[4-(3.5-dichloropyrid-4-ylcarboxamido)phenyl]-2-(3-benzoylbenzeneamino)Propionate

[0424] The title compound was prepared by a similar procedure to thecompound of Example 79, starting from 3-amino benzophenone: δH (CDCl₃)8.55 (2H, s), 7.72 (2H, d, J 8.5 Hz), 7.70-7.40 (6H, m), 7.30-7.00 (6H,m), 6.80 (1H, m), 4.40 (1H, br. m), 4.15 (2H, q, J 7.2 Hz), 3.40-3.20(2H, m), 1.20 (3H, t, J 7.2 Hz): m/z (EI⁺, 70V) 562.

EXAMPLE 88

[0425] Ethyl3-[4-(3.5-dichloropyrid-4-ylcarboxamido)phenyl]-2-(3-ethoxycarbonylbenzeneamino)Propionate

[0426] The title compound was prepared by a similar procedure to thecompound of Example 79, starting from ethyl 3-aminobenzoate: δH (CDCl₃)8.44 (2H, s), 7.50 (2H, d, J 8.4 Hz), 7.35 (1H, d, J 7.7 Hz), 7.30-7.10(4H, m), 6.77 (1H, m), 4.40 (1H, br. s), 4.31 (2H, q, J 7.2 Hz), 4.09(2H, m), 3.25-3.00 (2H, m), 1.33 (3H, t, J 7.2 Hz), 1.21 (3H, t, J 7.2Hz): m/z (EI⁺, 70V) 530.

EXAMPLE 89

[0427] -Ethyl3-[4-(3,5-dichloropyrid-4-ylcarboxamido)phenyl]-2-(5-chloro-4-propylthiopyridine-2-amino]propionate

[0428] The title compound was prepared by a similar procedure to thecompound of Example 79, starting from Intermediate 23: δH (CDCl₃) 8.53(2H, s), 8.11 (1H, s), 7.87 (1H, s), 7.54 (2H, d, J 8.4 Hz), 7.19 (2H,d, J 8.4 Hz), 6.17 (1H, s), 4.80 (1H, br. m), 4.21 (2H, q, 17.1 Hz),3.21 (1H, dd, J 14.0, 5.5 Hz), 3.09 (1H, dd, J 14.0, 5.7 Hz), 2.80 (2H,t, J 7.2 Hz), 1.74 (2H, m), 1.30 (3H, t,J 7.1 Hz), 1.07 (3H, t, J 7.3Hz): m/z (EI⁺, 70V) 568.

EXAMPLE 90

[0429] Ethyl3-[4-(3.5-dichloropyrid-4-ylcarboxamido)phenyl]-2-(5-chloro-4-propylsulphinylpyridine-2-amino)Propionate

[0430] The title compound was prepared by oxidation of the compound ofExample 89 with mCPBA: δH (CDCl₃) 8.55 (2H, s), 7.94 (2H, m), 7.52 (2H,d, J 8.4 Hz), 7.12 (2H, m), 6.82 (1H, d), 4.90 (1H, m), 4.20 (2H, m),3.40-3.00 (3H, m), 2.90-2.70 (1H, m), 2.00-1.60 (2H, m), 1.25 (3H, t, J7.2 Hz), 1.07 (3H, t, J 7.2 Hz): m/z (EI⁺, 70V) 584.

EXAMPLE 91

[0431] Ethyl3-[4-(3,5-dichloropyrid-4-ylcarboxamido)phenyl]-2-(5-chloro-4-propylsulphonylpyridine-2-amino]Propionate

[0432] The title compound was prepared by oxidation of the compound ofExample 89 with m-chloroperoxybenzoic acid: δH (CDCl₃) 8.56 (2H, s),8.19 (1H, s), 7.63 (1H, br. s), 7.51 (2H, d, J 8.4 Hz), 7.17 (2H, d, J8.4 Hz), 7.14 (1H, s), 5.34 (1H, br. m), 4.21 (2H, q, J 7.2 Hz), 3.30(2H, t, J 7.9 Hz), 3.35-3.10 (2H, m), 1.70 (2H, m), 1.29 (3H, t, J 7.2Hz), 1.01 (3H, t, J 7.5 Hz): m/z (EI⁺, 70V) 598.

EXAMPLE 92

[0433] Ethyl3-[4-(3,5-dichloropyrid-4-ylcarboxamido)phenyl]-2-(5-chloropyridine-2-amino]propionate

[0434] The title compound was prepared by a similar procedure to thecompound of Example 79, starting from 2-amino-5-chloro-pyridine: δH(CDCl₃) 8.56 (2H, s), 8.03 (1H, m), 7.59 (1H, m), 7.15 (2H, d, J 8.5Hz), 6.37 (1H, d, J 8.9 Hz), 4.84 (1H, br. m), 4.15 (2H, q, J 7.2 Hz),3.30-3.10 (2H, m), 1.20 (3H, t, J 7.2 Hz).

EXAMPLE 93

[0435] Ethyl3-[4-(3,5-dichloropyrid-4-ylcarboxamido)phenyl]-2-(4-propylthiopyridine-2-amino)Propionate

[0436] The title compound was prepared by a similar procedure to thecompound of Example 79, starting from 2-amino-4-propylthio-pyridine: δH(CDCl₃) 8.51 (2H, s), 8.40 (1H, br. s), 7.81 (1H, d, J 5.6 Hz), 7.49(2H, d, J 8.5 Hz), 7.13 (2H, d, J 8.5 Hz), 6.44 (1H, dd, J 5.6, 1.6 Hz),6.19 (1H, d, J 1.2 Hz), 4.95-4.72 (2H, m), 4.15 (2H, q, J 7.1 Hz),3.30-3.05 (2H, m), 2.80 (2H, t, J 7.4 Hz), 1.70 (2H, m), 1.22 (3H, t, J7.1 Hz), 1.01 (3H, t, J 7.4 Hz).

EXAMPLE 94

[0437] Ethyl3-[4-(3,5-dichloropyrid-4-ylcarboxamido)phenyl]-2-(4-propylsulphonylpyridine-2-amino)Propionate

[0438] The title compound was prepared by oxone oxidation of thecompound of Example 93: δH (CDCl₃) 8.56 (2H, s), 8.23 (1H, d, J 5.3 Hz),7.68 (1H, b r. m), 7.53 (2H, d, J 8.5 Hz), 7.20 (2H, d, J 8.5 Hz), 6.96(1H, m), 6.90 (1H, s), 4.90 (1H, br. m), 4.19 (2H, q, J 7.1 Hz),3.40-3.10 (2H, m), 3.01 (2H, m), 1.70 (2H, m), 1.25 (3H, t, J 7.2 Hz),1.02 (3H, t, J 7.5 Hz): m/z (EI⁺, 70V) 565.

EXAMPLE 95

[0439] Ethyl3-[4-(3,5-dichloropyrid-4-ylcarboxamido)phenyl]-2-(5-methoxycarbonyl-4-propylthiopyridine-2-amino)Propionate

[0440] The title compound was prepared by a similar procedure to thecompound of Example 79, starting from ethyl2-amino-4-propylthio-pyridine-5-carboxylate: δH (CDCl₃) 8.65 (1H, s),8.53 (2H, s) 8.05 (1H, br. s), 7.52 (2H, d, J 8.5 Hz), 7.20 (2H, d, J8.5 Hz), 6.20 (1H, s), 5.62 (1H, br. m), 4.92 (1H, br. m), 4.20 (2H, q,J 7.2 Hz), 3.90 (3H, s), 3.40-3.10 (2H, m), 2.72 (2H, t, J 7.4 Hz), 1.72(2H, m), 1.22 (3H, t, J 7.2 Hz), 1.10 (3H, t, J 7.4 Hz).

EXAMPLE 96

[0441] Ethyl3-[4-(3.5-dichloropyrid-4-ylcarboxamido)phenyl]-2-(5-methoxycarbonyl-4-propylsulphonylpyridine-2-amino)Propionate

[0442] The title compound was prepared by oxone oxidation of thecompound of Example 95: isolated crude and used without furtherpurification in Example 112.

EXAMPLE 97

[0443]3-[4-(3,5-Dichloropyrid-4-ylcarboxamido)phenyl]-2-(3-benzyloxybenzeneamino)Propanoic Acid

[0444] The title compound was prepared by lithium hydroxide hydrolysisof the compound of Example 79: δH (DMSO d₆) 10.84 (1H, s), 8.77 (2H, s),7.53 (2H, d, J 8.6 Hz), 7.42-7.26 (7H, m), 6.92 (1H, t, J 8.0 Hz), 6.17(3H, m), 4.97 (2H, s), 4.05 (1H, br. m), 3.29-2.89 (2H, m): m/z (EI⁺,70V) 536.

EXAMPLE 98

[0445]3-[4-(3,5-Dichloropyrid-4-ylcarboxamido)phenyl]-2-(3-benzyloxybenzeneamino)Propanoic Acid

[0446] The title compound was prepared by lithium hydroxide hydrolysisof the compound of Example 80: δH (DMSO d₆) 10.83 (1H, s), 8.77 (2H, s),7.53 (2H, d, J 8.5 Hz), 7.27 (2H, d, J 8.5 Hz), 6.95 (H, t, J 7.9 Hz),6.52-6.30 (3H, m), 4.10 (1H, br. m), 3.20-2.90 (2H, m), 2.80 (2H, t, J7.2 Hz), 1.52 (2H, m), 0.92 (3H, t, J 7.4 Hz): m/z (EI⁺, 70V) 504.

EXAMPLE 99

[0447]3-[4-(3,5-Dichloropyrid-4-ylcarboxamido)phenyl]-2-(4-carboxybenzeneamino)Propanoic Acid

[0448] The title compound was prepared by lithium hydroxide hydrolysisof the compound of Example 81: δH (DMSO d₆) 10.83 (1H, s), 8.77 (2H, s),7.65 (2H, d, J 8.7 Hz), 7.53 (2H, d, J 8.5 Hz), 7.27 (2H, d, J 8.5 Hz),6.76 (1H, d, J 8.6 Hz), 6.60 (2H, d, J 8.7 Hz), 4.22 (1H, br. m),3.30-2.95 (2H, m): m/z (EI⁺, 70V) 574.

EXAMPLE 100

[0449]3-[4-(3.5-Dichloropyrid-4-ylcarboxamido)phenyl]-2-(3-propylsulphonylbenzeneamino)Propanoic Acid

[0450] The title compound was prepared by lithium hydroxide hydrolysisof the compound of Example 82: δH (DMSO d₆) 10.84 (1H, s), 8.77 (1H, s),7.53 (2H, d, J 8.5 Hz), 7.29 (3H, m), 7.28 (1H, s), 7.01 (1H, d, J 7.6Hz), 6.86 (1H, d, J 8.1 Hz), 6.55 (1H, d, J 8.9 Hz), 4.20 (1H, br. m),3.17-3.11 (3H, m), 2.91 (1H, dd, J 13.8, 8.7 Hz), 1.48 (2H, m), 0.86(3H, t, J 7.5 Hz): m/z (EI⁺, 70V) 536.

EXAMPLE 101

[0451]3-[4-(3,5-Dichloropyrid-4-ylcarboxamido)phenyl]-2-(3-propylsulphinylbenzeneamino)Propanoic Acid

[0452] The title compound was prepared by lithium hydroxide hydrolysisof the compound of Example 83: δH (DMSO d₆) 12.75 (1H, br. s), 10.89(1H, s), 8.80 (2H, s), 7.55 (2H, d, J 8.5 Hz), 7.31 (2H, d, J 8.5 Hz),7.21 (1H, t, J 7.9 Hz), 6.84 (1H, s), 6.76-6.68 (2H, m), 6.42 (1H, br.m), 3.33 (2H, t, J 8.9 Hz), 3.30-2.50 (4H, m), 1.80-1.30 (2H, m), 0.93(3H, t, J 7.2 Hz): m/z (EI⁺, 70V) 520.

EXAMPLE 102

[0453]3-[4-(3,5-Dichloropyrid-4-ylcarboxamido)phenyl]-2-(4-carboxymethylbenzeneamino)Propanoic Acid

[0454] The title compound was prepared by lithium hydroxide hydrolysisof the compound of Example 84: δH (DMSO (6) 10.83 (1H, s), 8.76 (2H, s),7.53 (2H, d, J 8.5 Hz), 7.27 (2H, d, J 8.5 Hz), 6.92 (2H, d, J 8.5 Hz),6.51 (2H, d, J 8.5 Hz), 4.00 (1H, br. m), 2.95 (2H, m): m/z (EI⁺, 70V)488.

EXAMPLE 103

[0455]3-[4-(3,5-Dichloropyrid-4-ylcarboxamido)phenyl]-2-(3-acetylbenzeneamino)Propanoic Acid

[0456] The title compound was prepared by lithium hydroxide hydrolysisof the compound of Example 85: δH (DMSO d₆) 10.84 (1H, s), 8.77 (2H, s),7.53 (2H, d, 18.5 Hz), 7.29 (2H, d, J 8.5 Hz), 7.30-7.10 (3H, m), 6.82(1H, m), 6.20 (1H, br. m), 4.17 (1H, br. m), 3.20-2.90 (2H, m): m/z(EI⁺, 70V) 472.

EXAMPLE 104

[0457]3-[4-(3.5-Dichloropyrid-4-ylcarboxamido)phenyl]-2-(2-chloro-pyridine-3-amino)Propanoic Acid

[0458] The title compound was prepared by lithium hydroxide hydrolysisof the compound of Example 86: δH (DMSO d₆) 10.85 (1H, s), 8.77 (2H, s),7.75-7.50 (3H, m), 7.40-7.10 (4H, m), 5.28 (1H, d, J 8.4 Hz), 4.40 (1H,br. m), 3.15 (2H, d, J 5.9 Hz): m/z (EI⁺, 70V) 467.

EXAMPLE 105

[0459]3-[4-(3,5-Dichloropyrid-4-ylcarboxamido)phenyl]-2-(3-benzoylbenzeneamino)Propanoic Acid

[0460] The title compound was prepared by lithium hydroxide hydrolysisof the compound of Example 87: δH (DMSO d₆) 10:84 (1H, s), 8.77 (2H, s),7.90-7.40 (6H, m), 7.35-7.10 (3H, m), 7.05-6.80 (3H, m), 6.30 (1H, m),4.14 (1H, br. m), 3.20-2.80 (2H, m): m/z (EI⁺, 70V) 534.

EXAMPLE 106

[0461]3-[4-(3,5-Dichloropyrid-4-ylcarboxamido)phenyl]-2-(3-carboxybenzeneamino)Propanoic Acid

[0462] The title compound was prepared by lithium hydroxide hydrolysisof the compound of Example 88: δH (DMSO d₆) 12.61 (1H, br. s), 10.84(1H, s), 8.77 (2H, s), 7.54 (2H, d, J 8.5 Hz), 7.30 (2H, d, J 8.5 Hz),7.13 (3H, m), 6.78 (1H, m), 6.20 (1H, br. m), 4.12 (1H, br. m),3.20-2.90 (2H, m): m/z (EI⁺, 70V) 474.

EXAMPLE 107

[0463]3-[4-(3,5-Dichloropyrid-4-ylcarboxamido)phenyl]-2-(5-chloro-4-propylthiopyridine-2-amino)Propanoic Acid

[0464] The title compound was prepared by lithium hydroxide hydrolysisof the compound of Example 89: δH (DMSO d₆) 10.83 (1H, s), 8.77 (2H, s),7.81 (1H, s), 7.53 (2H, d, J 8.4 Hz), 7.23 (2H, d. J 8.4 Hz), 6.54 (1H,s), 4.56 (1H, m), 3.20-2.80 (4H, m), 1.63 (2H, m), 0.99 (3H, t, J 7.3Hz): m/z (EI⁺, 70V) 540.

EXAMPLE 108

[0465]3-[4-(3.5-Dichloropyrid-4-ylcarboxamido)phenyl]-2-(5-chloro-4-propylsulphinylpyridine-2-amino)Propanoic Acid

[0466] The title compound was prepared by lithium hydroxide hydrolysisof the compound of Example 90: δH (DMSO d₆) 12.48 (1H, br. s), 10.72(1H., s). 8.65 (1H, s), 7.86 (1H, s), 7.70-7.40 (3H, m), 7.20 (2H, m),6.88 (1H, m), 4.40 (1H, br. m), 3.10-2.90 (2H, m), 2.90-2.50 (2H, m),1.80-1.30 (2H, m), 0.85 (3H, m): m/z (EI⁺, 70V) 555.

EXAMPLE 109

[0467]3-[4-(3,5-Dichloropyrid-4-ylcarboxamido)phenyl]-2-(5-chloro-4-propvsulphonylpyridine-2-amino)Propanoic Acid

[0468] The title compound was prepared by lithium hydroxide hydrolysisof the compound of Example 91: δH (DMSO d₆) 10.84 (1H, s), 8.77 (2H, s),8.18 (1H, s), 7.80 (1H, br. m), 7.53 (2H, d, J 8.5 Hz), 7.26 (3H, m),4.60 (1H, m), 3.41 (2H, m), 3.30-3.10(1H, m), 3.10-2.80 (1H, m), 1.50(2H, m), 0.91 (3H, t, J 7.5 Hz): m/z (EI⁺, 70V) 571.

EXAMPLE 110

[0469]3-[4-(3,5-Dichloropyrid-4-ylcarboxamido)phenyl]-2-(5-chloropyridine-2-aminoPropanoic Acid

[0470] The title compound was prepared by lithium hydroxide hydrolysisof the compound of Example 92: δH (DMSO d₆) 12.40 (1H, br. s), 10.71(1H, s), 8.68 (2H, s), 7.79 (1H, s), 7.40 (2H, d, J 8.4 Hz), 7.28 (1H,m), 7.12 (2H, d, J 8.4 Hz), 6.91 (1H, d, J 8.2 Hz), 6.47 (1H, d, 18.9Hz), 4.45 (1H, m), 2.95 (1H, m), 2.77 (1H, m): m/z (EI⁺, 70V) 465.

EXAMPLE 111

[0471]3-[4-(3,5-Dichloropyrid-4-ylcarboxamido)phenyl]-2-(4-propylsulphonylpyridine-2-amino)Propanoic Acid

[0472] The title compound was prepared by lithium hydroxide hydrolysisof the compound of Example 94: δH (DMSO d₆) 10.86 (1H, s), 8.78 (2H, s),8.19 (1H, d, J 5.3 Hz), 7.55 (3H, m) 7.28 (2H, d, J 8.5 Hz), 7.07 (1H,s), 6.88 (1H, m), 4.64 (1H, br. m), 3.27 (2H, t, J 7.7 Hz), 3.12 (1H,m), 2.92 (1H, m), 1.50 (2H, m), 0.91 (3H, t, J 7.4 Hz): m/z (EI⁺, 70V)537.

EXAMPLE 112

[0473]S-3-[4-(3.5-Dichloropyrid-4-ylcarboxamido)phenyl]-2-(5-carboxy-4-propylsulphonylpyridine-2-amino)propanoicAcid

[0474] The title compound was prepared by lithium hydroxide hydrolysisof the compound of Example 96: δH (DMSO d₆) 13.0 (1H, br. s), 10.85 (1H,s), 8.78 (2H, s), 8.48 (1H, s), 7.55 (2H, d, J 8.6 Hz), 7.26 (3H, m),4.70 (1H, br. n), 3.66 (2H, t, J 7.7 Hz), 3.40-2.90 (2H, m), 1.58 (2H,m), 0.94 (3H, t, J 7.4 Hz): m/z (EI⁺, 70V) 581.

EXAMPLE 113

[0475]S-3-[4-(3,5-Dichloropyrid-4-ylcarboxamido)phenyl]-2-(5-carboxy-4-trifluormethylpyrimidin-2-ylamino)propanoicAcid

[0476] The title compound was prepared from Intermediate 3 and methyl2-chloro-4-(trifluoromethyl)pyrimidine 5-carboxylate, followed byhydrolysis: δH (DMSO d₆) 10.80 (1H, br s), 8.77 (1H, s), 8.75 (2H, s),8.51 and 8.38 (together 1H, d, J 8.0 Hz), 7.53 (2H, d, J 8.0 Hz), 7.32(2H, d, J 8.0 Hz), 4.65-4.50 (1H, br m), 3.21 (1H, dd, J 13.9, 3.9 Hz)and 3.03 (1H, dd, J 13.9, 10.4 Hz); m/z (EI⁺, 60V) 545.

EXAMPLE 114

[0477]S-ethyl-3-[4-(3,5-dichloro-1-oxido-4-pyridiniocarboxamido)phenyl]-2-(6-propylsulphonylpyrimidin-4-yl)propanoateandS-ethyl-3-[4-(3.5-dichloro-1-oxido-4-pyridiniocarboxamidophenyl]-2-(6-propylsulphonyl-1-oxido-4-pyrimidinio)Propanoate

[0478] A solution of the compound of Example 6 (14.0 g, 25.2 mmol) andmCPBA 30 g, 105 mmol assuming 60% pure) in dichloromethane (300 ml) werestirred at room temperature for 8H. The mixture was then treatd with 10%aqueous sodium sulfite solution (200 ml) and stirred for 5 mins. Afurther 200 ml of DCM was added before washing consecutively withsaturated aqueous NaHCO₃ (200 ml), brine (200 ml) and water (200 ml)dried (MgSO₄) and evaporated in vacua. The yellow solid obtained waschromatographed (silica; ethyl acetate→ethyl acetate/methanol (10%)) toafford

[0479]S-ethyl-3-[4-(3,5-dichloro-1-oxido-4-pyridiniocarboxamido)phenyl]-2-(6-propylsulphonylpyrimidin-4-yl)propanoate(3.0 g) andS-ethyl-3-[4-(3.5-dichloro-1-oxido-4-pyridinioarboxamidophenyl]-2-(6-propylsulphonyl-1-oxido-4-pyrimidinio)propanoate(5.5 g)

[0480] These materials were used without further characterisation inExamples 115 and 116.

EXAMPLE 115

[0481]S-3-[4-(3.5-Dichloro-1-oxido-4-pyridiniocarboxamido)phenyl]-2-(6-propylsulphonylpyrimidin-4-ylamino)propanoicAcid

[0482] A solution of the mono-N-oxide from Example 114 (3.0 g, 5.2 mmol)and lithium hydroxide monohydrate (0.32 g, 7.74 mmol) in THF/H₂O (1:1,100 ml) was stirred overnight at room temperature. THF was removed byevaporation in vacuo, and water (100 ml) added. The reaction mixture asmade pH3 with hydrochloric acid (1M) and then filtered and precipiatecollected and dried. Purification by recrystalisation (acetonitrile/H₂O)gave the title compound as a white powder (500 mg, 17%). δH (DMSO d₆)10.83 (1H, s), 8.72 (2H, s), 8.57 (1H, s), 8.45 (1H, d, J 7.7 Hz), 7.55(2H, d, J 8.5 Hz), 7.27 (2H, d, J 8.5 Hz), 7.22 (1H, s), 4.78 (1H, dt, J8.6, 5.0 Hz), 3.2 (m, obscured by H₂O), 3.00 (2H, dd, J 13.9, 9.11 Hz),1.59 (2H, q, J 7.6 Hz), 0.94 (3H, t, J 7.4 Hz); m/z (EI⁺, 80V) 554.

EXAMPLE 116

[0483]S-3-[4-(3,5-Dichloro-1-oxido-4-pyridiniocarboxamido)phenyl]2-(6-propylsulphonyl-1-oxido-4-pyrimidinioamino)propanoicAcid

[0484] A solution of the di-N-oxide from Example 114 (5.5 g, 9.2 mmol)and lithium hydroxide monohydrate (0.6 g, 13.8 nmol) in THF/H₂O 1:1 (100ml) was stirred overnight at room temperature. The THF was then removedin vacuo and the remaining solution diluted with H₂O (100 ml), before 1MHCl added to make the pH3. The precipitate was collected by filtration,dried to give the title compound as a pale yellow solid (40 g, 76%). δH(DMSO d₆) 10.83 (1H, s), 8.72 (2H, s), 8.57 (1H, s), 8.45 (1H, d, J 7.7Hz), 7.55 (2H, d, J 8.5 Hz), 7.27 (2H, d, J 8.5 Hz), 7.22 (1H, s), 4.78(1H, m), 3.2 (m, obscured by H₂O), 1.60 (2H, q,J 7.6 Hz), 0.93 (3H, t, J7.4 Hz); m/z (EI⁺, 80V) 572.

EXAMPLE 117

[0485]3-[4-(3.5-Dichloropyrid-4-ylcarboxamido)phenyl]-2-(6-propylpyrid-2-ylamino)propanoicAcid

[0486] A mixture of Intermediate 25 (150 mg), dirhodiumtetraacetate,(1.8 mg, 5.1 μmols) and 2-amino-6-propylpyridine in anhydrous toluene(2.5 mL) was agitated at ambient temperature for 0.5 h then at 80° C.for 6 h. The resin was filtered and then washed with DCM, DMF, methanol,water, methanol, DMF and DCM. The resin was treated with 50%trifluoroacetic acid in DCM (4.0 ml) for 3 h with agitation andfiltered. The resin was then washed with a 4.0 ml portion of DCM. Thecombined filtrate was evaporated in vacuo to give the crude product (48mg) which was purified by preparative HPLC to afford the title compound(20.7 mg). HPLC-MS Retention time 2.19 min; MH⁺ 473.

[0487] HPLC-MS

[0488] HPLC-MS was performed on a Hewlett Packard 1100/MSD ES SingleQuadropole system with diode array detector using a Luna C18(2) 50×2.0mm (3 μm) column, running a gradient of 95% [0.1% aqueous formic acid],5% [0.1% formic acid in acetonitrile] to 10% [0.1% aqueous formic acid],90% [0.1% formic acid in acetonitrile] over 2 min, then maintaining themobile phase at that ratio for a further 1 min. Flow rate 0.8 ml/min. MSwas acquired by API electrospray in positive ion mode, at 70V, scanningfrom 150 to 750 amu.

[0489] The following compounds of Examples 118-168 were prepared in asimilar manner to the compound of Example 117, each using the startingmaterial shown in place of 2-amino-6-propylpyridine.

EXAMPLE 118

[0490]3-[4-(3,5-Dichloropyrid-4-ylcarboxamido)phenyl]-2-(3-methylisoxazol-5-ylamino)propanoicAcid

[0491] 5-Amino-3-methylisoxazole gave the title compound (0.7 mg)HPLC-MS Retention time 2.37 min; MH⁺ 435.

EXAMPLE 119

[0492]3-[4-(3,5-Dichloropyrid-4-ylcarboxamido)phenyl-2-[2-acetyl-5-(4-chlorophenyl)thien-3-ylamino]propanoicAcid

[0493] 2-Acetyl-3-amino-5-(4-chlorophenyl)thiophene gave the titlecompound (2.6 mg) HPLC-MS Retention time 2.90 min; MH⁺ 588.

EXAMPLE 120

[0494]3-[4-(3.5-Dichloropyrid-4-ylcarboxamido)phenyl]-2-(2-methylquinol-6-ylamino)propanoicAcid

[0495] 6-Amino-2-methylquinoline gave the title compound (5.0 mg)HPLC-MS Retention time 2.17 min; MH⁺ 495.

EXAMPLE 121

[0496]3-[4-(3,5-Dichloropyrid-4-ylcarboxamido)phenyl]-2-(quinol-6-ylamino)Propanoic Acid

[0497] 6-Aminoquinoline gave the title compound (3.3 mg) HPLC-MSRetention time 2.15 min; MH⁺ 481

EXAMPLE 122

[0498]3-[4-(3.5-Dichloropyrid-4-ylcarboxamido)phenyl]-2-(quinol-2-ylamino)propanoicAcid

[0499] 2-Aminoquinoline gave the title compound (4.3 mg) HPLC-MSRetention time 2.20 min; MH⁺ 481.

EXAMPLE 123

[0500]3-[4-(3,5-Dichloropyrid-4-ylcarboxamido)phenyl]-2-(quinol-3-ylamino)propanoicAcid

[0501] 3-Aminoquinoline gave the title compound (5.1 mg) HPLC-MSRetention time 2.22 min; MH⁺ 481.

EXAMPLE 124

[0502]3-[4-(3.5-Dichloropyrid-4-ylcarboxamido)phenyl]-2-[4-chloro-2-(methylthio)pyrimidin-6-ylamino]propanoic Acid

[0503] 6-Amino-4-chloro-2-(methylthio)pyrimidine gave the title compound(1.4 mg) HPLC-MS Retention time 2.63 min; MH⁺ 512.

EXAMPLE 125

[0504]3-[4-(3,5-Dichloropyrid-4-ylcarboxamido)phenyl]-2-(3,5-dichloro-2,6-difluoropyrid-4-ylamino)propanoicAcid

[0505] 4-Amino-3,5-dichloro-2,6-difluoropyridine gave the title compound(1.1 mg) HPLC-MS Retention time 2.81 min; MH⁺ 535.

EXAMPLE 126

[0506]3-[4-(3,5-Dichloropyrid-4-ylcarboxamido)phenyl]-2-(4,6-dimethylpyrid-2-ylamino)propanoicAcid

[0507] 2-Amino-4,6-dimethylpyridine gave the title compound (3.9 mg)HPLC-MS Retention time 2.11 min; MH⁺ 459,

EXAMPLE 127

[0508]3-[4-(3.5-Dichloropyrid-4-ylcarboxamido)phenyl]-2-(4,6-dimethoxypyrimidin-2-ylamino)propanoicAcid

[0509] 2-Amino-4,6-dimethoxypyrimidine gave the title compound (3.0 mg)HPLC-MS Retention time 2.56 min; MH⁺ 492.

EXAMPLE 128

[0510]3-[4-(3,5-Dichloropyrid-4-ylcarboxamido)phenyl]-2-(2-methylpyrid-4-ylamino)propanoicAcid

[0511] 4-Amino-2-methylpyridine gave the title compound (1.3 mg) HPLC-MSRetention time 2.09 min; MH⁺ 445.

EXAMPLE 129

[0512]3-[4-(3.5-Dichloropyrid-4-ylcarboxamido)phenyl]-2-(6-chloropyrid-3-ylamino)propanoicAcid

[0513] 3-Amino-6-chloropyridine gave the title compound (2.7 mg) HPLC-MSRetention time 2.52 min; MH⁺ 465.

EXAMPLE 130

[0514]3-[4-(3.5-Dichloroprid-4-ylcarboxamido)phenyl]-2-(5-bromopryid-2-ylamino)propanoicAcid

[0515] 2 Amino-5-bromo-2-pyridine gave the title compound (2.6 mg)HPLC-MS Retention time 2.60 min; MH⁺ 510.

EXAMPLE 131

[0516]3-[4-(3.5-Dichloropyrid-4-ylcarboxamido)phenyl]-2-(2,6-dichloropyrid-4-ylamino)propanoicAcid

[0517] 4-Amino-2,6-dichloropyridine gave the title compound (1.6 mg)HPLC-MS Retention time 2.62 min; MH⁺ 499

EXAMPLE 132

[0518]3-[4-(3.5-Dichloropyrid-4-ylcarboxamido)phenyl]-2-(3.5-dibromopyrid-2-ylamino)propanoicAcid

[0519] 2-Amino-3,5-dibromopyridine gave the title compound (0.2 mg)HPLC-MS Retention time 2.83 min; MH⁺ 589.

EXAMPLE 133

[0520]3-[4-(3,5-Dichloropyrid-4-ylcarboxamido)phenyl]-2-(4,6-dimethylpyrimidin-2-ylamino)propanoicAcid

[0521] 2-Amino-4,6-dimethylpyrimidine gave the title compound (2.7 mg)HPLC-MS Retention time 2.23 min; MH⁺ 450.

EXAMPLE 134

[0522]3-[4-(3,5-Dichloropyrid-4-ylcarboxamido)phenyl]-2-(3-ethyl-6-methylpyrid-2-ylamino)propanoicAcid

[0523] 2-Amino-3-ethyl-6-methylpyridine gave the title compound (1.3 mg)HPLC-MS Retention time 2.23 min; MH⁺ 473.

EXAMPLE 135

[0524]3-[4-(3.5-Dichloropyrid-4-ylcarboxamido)phenyl]-2-(4-ethylpyrid-2-ylamino)propanoicAcid

[0525] 2-Amino-4-ethylpyridine gave the title compound (0.8 mg) HPLC-MSRetention time 2.14 min; MH⁺ 459.

EXAMPLE 136

[0526]3-[4-(3.5-Dichloropyrid-4-ylcarboxamido)phenyl]-2-(6-ethylpyrid-2-ylamino)propanoicAcid

[0527] 2-Amino-6-ethylpyridine gave the title compound (2.4 mg) HPLC-MSRetention time 2.14 min; MH⁺ 459.

EXAMPLE 137

[0528]3-[4-(3,5-Dichloropyrid-4-ylcarboxamido)phenyl]-2-(2,5-dichloropyrid-3-ylamino)Propanoic Acid

[0529] 3-Amino-2,5-dichloropyridine gave the title compound (1.0 mg)HPLC-MS Retention time 2.68 min; MH⁺ 501.

EXAMPLE 138

[0530]3-[4-(3.5-Dichloropyrid-4-ylcraboxamido)phenyl]-2-(4-trifluoromethylpyrimidin-2-ylamino)Propanoic Acid

[0531] 2-Amino-4-trifluoromethylpyrimidine gave the title compound (1.2mg) HPLC-MS Retention time 2.62 min; MH⁺ 500.

EXAMPLE 139

[0532]3-[4-(3.5-Dichloropyrid-4-ylcarboxamido)pheny]-2-(5-bromopyrimidin-2-ylamino)propanoicAcid

[0533] 2-Amino-5-bromopyrimidine gave The title compound (0.6 mg)HPLC-MS Retention time 2.56 min; MH⁺ 511.

EXAMPLE 140

[0534]3-[4-(3.5-Dichloropyrid-4-ylcarboxamido)phenyl]-2-(2-chloropyrid-3-ylamino)propanoicAcid

[0535] 3-Amino-2-chloropyridine gave the title compound (2.5 mg) HPLC-MSRetention time 2.52 min; MH⁺ 465.

EXAMPLE 141

[0536]3-[4-(3,5-Dichloropyrid-4-ylcarboxamido)phenyl]-2-[4-trifluoromethyl-6-methylpyrimidin-2-ylamino)propanoicAcid

[0537] 2-Amino-4-trifluoromethyl-6-methylpyrimidine gave the titlecompound (3.1 mg) HPLC-MS Retention time 2.65 min; MH⁺ 514.

EXAMPLE 142

[0538]3-[4-(3,5-Dichloropyrid-4-ylcarboxamido)phenyl]-2-(4,6-dichloro-2-methylpyrimidin-5-ylamino)Propanoic Acid

[0539] 5 Amino-4,6-dichloro-2-methylpyrimidine gave the title compound(1.7 mg) HPLC-MS Retention time 2.55 min; MH⁺ 516.

EXAMPLE 143

[0540]3-[4-(3,5-Dichloropyrid-4-ylcarboxamido)phenyl]-2-(4,6-dimethoxypyrimidin-5-ylamino)Propanoic Acid

[0541] 5-Amino-4,6-Dimethoxypyrimidine gave the title compound (0.9 mg)HPLC-MS Retention time 2.43 min; MH⁺ 492.

EXAMPLE 144

[0542]3-[4-(3.5-Dichloropyrid-4-ylcarboxamido)phenyl]-2-3-benzyloxypyrid-2-ylamino)Propanoic Acid

[0543] 2-Amino-3-benzyloxypyridine gave the title compound (2.8 mg)HPLC-MS Retention time 2.33 min; MH⁺ 537.

EXAMPLE 145

[0544]3-[4-(3.5-Dichloropyrid-4-ylcarboxamido)phenyl]-2-[4-(5-chloropyrid-2-yloxy)phenylamino]Propanoic Acid

[0545] 4-(5-Chloropyrid-2-yloxy)aniline gave the title compound (1.7 mg)HPLC-MS Retention time 2.73 min; MH⁺ 557.

EXAMPLE 146

[0546]3-[4-(3,5-Dichloropyrid-4-ylcarboxamido)phenyl]-2-(2-chloro-5-phenylpyrid-6-ylamino)Propanoic Acid

[0547] 6-Amino-2-chloro-5-phenylpyridine gave the title compound (0.5mg) HPLC-MS Retention time 2.87 min MH⁺ 541

EXAMPLE 147

[0548]3-[4-(3.5-Dichloropyrid-4-ylcarboxamido)phenyl]-2-(1-oxidopyrid-3-ylamino)propanoicAcid

[0549] 3-Aminopyridine-1-oxide gave the title compound (1.1 mg) HPLC-MSRetention time 2.16 min; MH⁺ 447.

EXAMPLE 148

[0550]3-[4-(3,5-Dichloropyrid-4-ylcarboxamido)phenyl]-2-[4-(4-methylphenyl)pyrimidin-2-ylamino]Propanoic Acid

[0551] 2-Amino-4-(4-methylphenyl)pyrimidine gave the title compound (2.2mg) HPLC-MS Retention time 2.57 min; MH⁺ 522.

EXAMPLE 149

[0552]3-[4-(3,5-Dichloropyrid-4-ylcarboxamido)phenyl]-2-[4-(4-chlorophenyl)pyrimidin-2-ylamino]propanoicAcid

[0553] 2-Amino-4-(4-chlorophenyl)pyrimidine gave the title compound (0.8mg) HPLC-MS Retention time 2.67 min; MH⁺ 542.

EXAMPLE 150

[0554]3-[4-(3.5-Dichloropyrid-4-ylcarboxamido)phenyl]-2-(4-chloro-6-pyrrolidinopyrimidin-2-ylamino)Propanoic Acid

[0555] 2-Amino-4-chloro-6-pyrrolidinopyrimidine gave the title compound(3.2 mg) HPLC-MS Retention time 2.59 min; MH⁺ 537.

EXAMPLE 151

[0556]3-[4-(3.5-Dichloropyrid-4-ylcarboxamido)phenyl]-2-(4-(chlorodifluoromethyl)-6-methylpyrimidin-2-ylamino)propanoicacid 2-Amino-4-(chlorodifluoromethyl)-6-methylpyrimidine gave the titlecompound (0.6 mg) HPLC-MS Retention time 2.66 min; MH⁺ 532.

EXAMPLE 152

[0557]3-[4-(3.5-Dichloropyrid-4-ylcarboxamido)phenyl]-2-(3.5-difluorophenylamino)propanoicAcid

[0558] 3,5-Difluoroaniline gave the title compound (1 mg) HPLC-MSRetention 2.67 min; MH⁺ 466.

EXAMPLE 153

[0559]3-[4-(3,5-Dichloropyrid-4-ylcarboxamido)phenyl]-2-(2.4.6-trimethylphenylamino)propanoicAcid

[0560] 2,4,6-Trimethylaniline gave the title compound (4 mg) HPLC-MSRetention 2.77 min; MH⁺ 472.

EXAMPLE 154

[0561]3-[4-(3.5-Dichloropyrid-4-ylcarboxamido)phenyl]-2-(2.6-diethylphenylamino)propanoicAcid

[0562] 2,6-Diethylaniline gave the title compound (6 mg) HPLC-MSRetention 2.85 min; MH⁺ 486

EXAMPLE 155

[0563]3-[4-(3.5-Dichloropyrid-4-ylcarboxamido)phenyl]-2-(3-(trifluoromethyl)phenylamino)propanoicAcid

[0564] 3-(Trifluoromethyl)aniline gave the title compound (3 mg) HPLC-MSRetention 2.74 min; MH⁺ 498.

EXAMPLE 156

[0565]3-[4-(3.5-Dichloropyrid-4-ylcarboxamido)phenyl]-2-(2-propylphenylamino)propanoicAcid

[0566] 2-Propylaniline gave the title compound (2 mg) HPLC-MS Retention2.80 min; MH⁺ 472.

EXAMPLE 157

[0567]3-[4-(3.5-Dichloropyrid-4-ylcarboxamido)phenyl]-2-(4-ethylphenylamino)propanoicAcid

[0568] 4-Ethylaniline gave the title compound (2 mg) HPLC-MS Retention2.72 min; MH⁺ 458.

EXAMPLE 158

[0569]3-[4-(3,5-Dichloropyrid-4-ylcarboxamido)phenyl]-2-(3,4,5-trichlorophenylamino)propanoicAcid

[0570] 3,4,5-Trichloroaniline gave the title compound (1 mg) HPLC-MSRetention 2.86 min; MH⁺ 532.

EXAMPLE 159

[0571]3-[4-(3.5-Dichloropyrid-4-ylcarboxamido)phenyl]-2-(3,4,5-trifluorophenylamino)propanoicAcid

[0572] 3,4,5-Trifluoroaniline gave the title compound (3 mg) HPLC-MSRetention 2.70 min; MH⁺ 484

EXAMPLE 160

[0573]3-[4-(3.5-Dichloropyrid-4-ylcarboxamido)phenyl]-2-(2-benzylphenylamino)propanoicAcid

[0574] 2-Benzylaniline gave the title compound (1 mg) HPLC-MS Retention2.84 min; MH⁺ 520

EXAMPLE 161

[0575]3-[4-(3,5-Dichloropyrid-4-ylcarboxamido)phenyl]-2-(3,5-bis(trifluoromethyl)phenylamino)propanoicAcid

[0576] 3,5-Bis(trifluoromethyl)aniline gave the title compound (1 mg)HPLC-MS Retention 2.87 min; MH⁺ 566.

EXAMPLE 162

[0577]3-[4-(3,5-Dichloropyrid-4-ylcarboxamido)phenyl]-2-(4-isopropylphenylamino)propanoicAcid

[0578] 4-Isopropylaniline gave the title compound (2 mg) HPLC=MSRetention 2.80 min; MH⁺ 472.

EXAMPLE 163

[0579]3-[4-(3.5-Dichloropyrid-4-ylcarboxamido)phenyl]-2-(3-trifluoromethoxyphenylamino)propanoicAcid

[0580] 3-Trifiuoromethoxyaniline gave the title compound (4 mg) HPLC-MSRetention 2.76 min; MH⁺ 514.

EXAMPLE 164

[0581]3-[4-(3.5-Dichloropyrid-4-ylcarboxamido)phenyl]-2-(2-fluoro-5-(trifluoromethyl)phenylamino)propanoicAcid

[0582] 2-Fluoro-5-(trifluoromethyl)aniline gave the title compound (4mg) HPLC-MS Retention 2.75 min; MH⁺ 516.

EXAMPLE 165

[0583]3-[4-(3,5-Dichloropyrid-4-ylcarboxamido)phenyl]-2-(3-chloro-4-fluorophenylamino)propanoicacid 3-Chloro-4-fluoroaniline gave the title compound (6 mg) HPLC-MSRetention 2.70 min; MH⁺ 482.

EXAMPLE 166

[0584]3-[4-(3,5-Dichloropyrid-4-ylcarboxamido)phenyl]-2-(3-nitrophenylamino)propanoicAcid

[0585] 3-Nitroaniline gave the title compound (2 mg) HPLC-MS 2.62 min;MH⁺ 475.

EXAMPLE 167

[0586]3-[4-(3,5-Dichloropyrid-4-ylcarboxamido)phenyl]-2-(2,3,5,6-tetrafluorophenylamino)propanoicAcid

[0587] 2,3,5,6-tetrafluoroaniline gave the title compound (1 mg) HPLC-MSRetention 2.72 min; MH⁺ 502.

EXAMPLE 168

[0588]3-[4-(3,5-Dichloropyrid-4-ylcarboxamido)phenyl]-2-(3-chlorophenylamino)propanoicAcid

[0589] 3-Chloroaniline gave the title compound (1 mg) HPLC-MS Retention2.70 min; MH⁺ 464.

[0590] The following compound of this invention was prepared as follows:

EXAMPLE 169 Synthesis ofN-[3-(5-(2,2,2-trifluoroethyl)pyrimidin-4-yl)amino]-2-(4-(N′,N′-dimethylaminocarbonyloxy)phenyl)propionicAcid

[0591]

[0592] 3-Amino-2(R)-(4-hydroxyphenyl)propionic acid is prepared as perthe procedure of Arvanitis, et al., J. Chem. Soc., Perkin Trans.,1(8):1459 (1998). This compound is converted via conventional methods toprovide for ethyl N-Boc 3-amino-2(R)-(4-hydroxyphenyl)propionic acid.This compound is converted by method A below to provide for ethyl N-Boc2(R)-(4-N,N-dimethylamino-carbonyloxyphenyl)propionate. Conventionaldeprotection provides for ethyl2(R)-(4-N,N-dimethylamino-carbonyloxyphenyl)propionate.

[0593] 2,2,2-Trifluoroethyl (prepared accordingly to Gassman, et al. J.Org. Chem., 1984, 49(12), 2258-2273) is converted via sequentialapplication of methods B, C, and D (as below) to give4,6-dichloro-5-(z,2,2-trifluoroethyl)pyrimidine.

[0594] Ethyl 2(R)-(4-N,N-dimethylaminocarbonyloxyphenyl)propionate and4,6-dichloro-5-(2,2,2-trifluoroethyl)pyrimidine were coupled via methodE and the product was transformed via sequential application of methodsF and G to give the title compound.

[0595] Method A

[0596] Carbamate Formation Procedure I

[0597] Into a reaction vial are combined 15.2 mmol, 1.0 eq. of thestarting hydroxy compound and 1.86 g (15.2 mmol, 1.0 eq) DMAP. Methylenechloride (50 mL), triethylamine (2.12 mL, 1.54 g, 15.2 mmol, 1.0 eq),and dimethylcarbamyl chloride (1.68 mL, 1.96 g, 18.2 mmol, 1.2 eq) arethen added. The vial is capped tightly, and the reaction solution isswirled to obtain a homogeneous solution. The reaction solution is thenheated to 40° C. After 48 h, TLC of the resulting colorless solutionindicates complete conversion. The work-up of the reaction solution isas follows: 50 mL EtOAc and 50 mL hexanes is added to the reactionmixture, and the resulting mixture is washed with 0.5 M citric acid(3×50 mL), water (2×50 mL),10% K₂CO₃ (2×50 mL), and sat. NaCl (1×50 mL);dried with MgSO₄, filtered and evaporated to afford the desiredcompound.

Method B Preparation of Dimethyl 2-Alkylmalonate

[0598] To a suspension of sodium hydride 60% dispersion in mineral oil(1.1 eq) in anhydrous THF is added slowly with stirring dimethylmalonate (1.1 eq), causing the evolution of gas. To the resultingsolution is added a bromoalkane, iodoalkane, ortrifluoromethanesulfonyloxyalkane (1.0 eq), and the mixture is heated to50° C. for 48 h, at which point TLC indicated consumption of thebromoalkane, iodoalkane, or trifluoromethanesulfonyloxyalkane. Themixture is diluted with diethyl ether and washed with 70% saturatedsodium chloride. The organic extracts are treated with anhydrousmagnesium sulfate, filtered, and evaporated to afford a dimethyl2-alkylmalonate of sufficient purity for immediate conversion to a5-alkyl-4,6-dihydroxypyrimidine.

Method C Preparation of 5-Alkyl-4,6-dihydroxypyrimidine

[0599] To a diethyl 2-alkylmalonate or a dimethyl 2-alkylmalonate (1.0eq) is added formamidine acetate (1.0 eq) and 25% sodium methoxide inmethanol (3.3 eq). The resulting slurry is stirred vigorously and heatedto 60° C. for 4 h, and then allowed to cool. The slurry is diluted withwater, and acidified to pH=2 by addition of HCl. The resultingprecipitate is collected by filtration, is washed with water, and isdried under vacuum, to afford a 5-alkyl-4,6-dihydroxypyrimidine ofsufficient purity for immediate conversion to a5-alkyl-4,6-dichloropyrimidine.

Method D Preparation of 5-Alkyl-4,6-dichloropyrimidine or5-Alkoxy-4-chloropyrimidine

[0600] To a 5-alkyl-4,6-dihydroxypyrimidine or a5-alkoxy-4-hydroxypyrimidine (1.0 eq) are added phosphorus oxychloride(15.0 eq) and N,N-dimethylaniline (1.0 eq), and the mixture is heated to100° C. for 3 h, and then is allowed to cool. The resulting solution ispoured onto ice, and the mixture is extracted with dichloromethane. Theorganic extracts are treated with anhydrous magnesium sulfate, filtered,and is evaporated to afford a 5-alkyl-4,6-dichloropyrimidine or a5-alkoxy-4-chloropyrimidine of sufficient purity for immediateconversion to a 5-alkyl-4-N-alkylamino-6-chloropyrimidine or a5-alkoxy-4-N-alkylaminopyrimidine.

Method E Preparation of 5-Alkyl-4-N-alkylamino-6-chloropyrimidine or5-Alkoxy-4-N-alkylaminopyrimidine

[0601] To a solution of a 5-alkyl-4,6-dichloropyrimidine or a5-alkoxy-4-chloropyrimidine (1.0 eq) in ethanol are added an alkyl amine(1.2 eq, typically L-4-(N,N-dimethylcarbamyloxy)-phenylalaninetert-butyl ester) and diisopropylethylamine (2.0 eq). The mixture issealed in a pressure tube and is heated to 120° C. for 48 h, at whichpoint TLC indicates consumption of the 5-alkyl-4,6-dichloropyrimidine orthe 5-alkoxy-4-chloropyrimidine. The mixture is evaporated, and theresidue is partitioned between ethyl acetate and pH=4.5 citrate buffer.The organic extracts are washed with saturated sodium chloride, treatedwith anhydrous magnesium sulfate, filtered, and evaporated. The residueis purified by chromatography on silica gel using ethyl acetate andhexanes to afford a pure 5-alkyl-4-N-alkylamino-6-chloropyrimidine or5-alkoxy-4-N-alkylaminopyrimidine.

Method F Preparation of 5-Alkyl-4-N-alkylaminopyrimidine (Procedure I)

[0602] A suspension of 5-alkyl-4-N-alkylamino-6-chloropyrimidine (1.0eq), and an equal mass 10% palladium on carbon, and sodium bicarbonate(5.0 eq) in methanol is shaken under 55 psi hydrogen gas for 16 h, atwhich point TLC indicates consumption of the5-alkyl-4-N-alkylamino-6-chloropyrimidine. The mixture is filteredthrough Celite and evaporated to give a residue, which is partitionedbetween ethyl acetate and 70% saturated sodium chloride. The organicextracts are treated with anhydrous magnesium sulfate, filtered, andevaporated. The residue is purified by chromatography on silica gelusing ethyl acetate and hexanes to afford a pure5-alkyl-4-N-alkylaminopyrimidine.

Method G Ester Hydrolysis Procedure II

[0603] To a chilled (0° C.) THF/H₂O solution (2:1, 5-10 mL) of theappropriate ester is added LiOH (1.1 equivalents). The temperature ismaintained at 0° C. and the reaction is complete in 1-3 hours. Thereaction mixture is concentrated and the residue is taken up into H₂Oand the pH is adjusted to 2-3 with aqueous HCl. The product is extractedwith ethyl acetate and the combined organic phase is washed with brine,dried over MgSO₄, filtered and concentrated to yield the desired acid.

[0604] The following assays can be used to demonstrate the potency andselectivity of the compounds according to the invention. In each ofthese assays an IC₅₀ value was determined for each test compound andrepresents the concentration of compound necessary to achieve 50%inhibition of cell adhesion where 100%=adhesion assessed in the absenceof the test compound and 0%=absorbance in wells that did not receivecells.

[0605] α₄β₁ Integrin-Dependent Jurkat Cell Adhesion to VCAM-Ig

[0606] 96 well NUNC plates were coated with F(ab)₂ fragment goatanti-human IgG Fcγ-specific antibody [Jackson Immuno Research109-006-098: 100 μl at 2 μg/ml in 0.1M NaHCO₃, pH 8.4], overnight at 4°.The plates were washed (3×) in phosphate-buffered saline (PBS) and thenblocked for 1 h PBS/1% BSA at room temperature on a rocking platform.After washing (3× in PBS) 9 ng/ml of purified 2d VCAM-Ig diluted inPBS/1% BSA was added and the plates left for 60 minutes at roomtemperature on a rocking platform. The plates were washed (3× in PBS)and the assay then performed at 370 for 30 min in a total volume of 200μl containing 2.5×10⁵ Jurkat cells in the presence or absence oftitrated test compounds.

[0607] Each plate was washed (2×) with medium and the adherent cellswere fixed with 100 μl methanol for 10 minutes followed by another wash.100 μl 0.25% Rose Bengal (Sigma R4507) in PBS was added for 5 minutes atroom temperature and the plates washed (3×) in PBS. 100 μl 50% (v/v)ethanol in PBS was added and the plates left for 60 min after which theabsorbance (570 nm) was measured.

[0608] α₄β₇ Integrin-Dependent JY Cell Adhesion to MAdCAM-Ig

[0609] This assay was performed in the same manner as the α₄β₁ assayexcept that MAdCAM-Ig (150 ng/ml) was used in place of 2d VCAM-Ig and asubline of the β-lympho blastoid cell-line JY was used in place ofJurkat cells. The IC₅₀ value for each test compound was determined asdescribed in the α₄β₁ integrin assay.

[0610] α₅β₁ Integrin-Dependent K562 Cell Adhesion to Fibronectin

[0611] 96 well tissue culture plates were coated with human plasmafibronectin (Sigma F0895) at 5 μg/ml in phosphate-buffered saline (PBS)for 2 hr at 37° C. The plates were washed (3×in PBS) and then blockedfor 1 h in 100 μl PBS/1% BSA at room temperature on a rocking platform.The blocked plates were washed (3× in PBS) and the assay then performedat 37° C. in a total volume of 200 μl containing 2.5×10⁵ K562 cells,phorbol-12-myristate-13-acetate at 10 ng/ml, and in the presence orabsence of titrated test compounds. Incubation time was 30 minutes. Eachplate was fixed and stained as described in the α₄β₁ assay above.

[0612] α_(m)β₂-Dependent Human Polymorphonuclear Neutrophils Adhesion toPlastic

[0613] 96 well tissue culture plates were coated with RPMI 1640/10% FCSfor 2 h at 37° C. 2×10⁵ freshly isolated human vencus polymorphonuclearneutrophils (PMN) were added to the wells in a total volume of 200 μl inthe presence of 10 ng/ml phorbol-12-myristate-13-acetate, and in thepresence or absence of test compounds, and incubated for 20 min at 37°C. followed by 30 min at room temperature. The plates were washed inmedium and 100 μl 0.1% (w/v) HMB (hexadecyl trimethyl ammonium bromide,Sigma H5882) in 0.05M potassium phosphate buffer, pH 6.0 added to eachwell. The plates were then left on a rocker at room temperature for 60min. Endogenous peroxidase activity was then assessed using tetramethylenzidine (TMB) as follows: PMN lysate samples mixed with 0.22%H₂O₂Sigma) and 50 g/ml TMB (Boehringer Mannheim) in 0.1M sodiumacetate/citrate buffer, pH 6.0 and absorbance measured at 630 nm.

[0614] α11b/β₃-Dependent Human Platelet Aggregation

[0615] Human platelet aggregation was assessed using impedanceaggregation on the Chronolog Whole Blood Lumiaggregometer. Humanplatelet-rich plasma (PRP) was obtained by spinning fresh human venousblood anticoagulated with 0.38% (v/v) tri-sodium citrate at 220×g for 10min and diluted to a cell density of 6×10⁸/ml in autologous plasma.Cuvettes contained equal volumes of PRP and filtered Tyrode's buffer(g/liter: NaCl 8.0; MgCl₂.H₂O 0.427; CaCl₂ 0.2; KCl 0.2; D-glucose 1.0;NaHCO₃ 1.0; NaHPO₄.2H₂O 0.065). Aggregation was monitored followingaddition of 2.5 μM ADP (Sigma) in the presence or absence of inhibitors.

[0616] In the above assays the preferred compounds of the inventiongenerally have IC₅₀ values in the α₄β₇ and α₄β₇ assays of 1 μM andbelow. In the other assays featuring α integrins of other subgroups thesame compounds had IC₅₀ values of 50 μM and above thus demonstrating thepotency and selectivity of their action against α₄ integrins.

What is claimed is:
 1. A compound of formula I:

wherein R¹ and R² are independently selected from the group consistingof hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,cycloalkyl, substituted cycloalkyl, or R¹ and R², together with thenitrogen atom to which they are attached, are joined to form anoptionally substituted heterocyclic ring provided that said substitutedalkyl, substituted alkenyl and substituted cycloalkyl do not carry anaryl, substituted aryl, heteroaryl or substituted heteroaryl group; R⁴and R⁵ are independently selected from the group consisting of-L²(Alk³)_(t)L³(R⁷)_(u) in which L² and L³ are independently a covalentbond or a linker atom or group, t is zero or the integer 1, u is aninteger 1, 2, or 3, Alk³ is an aliphatic or heteroaliphatic chain and R⁷is hydrogen or halogen atom or a group selected from alkyl, —OR⁸ [whereR⁸ is a hydrogen atom or an optionally substituted alkyl group], —SR⁸,—NR⁸R⁹ [where R⁸ is a hydrogen atom or an optionally substituted alkylgroup], —NO₂, —CN, —CO₂R⁸, —SO₃H, —SOR⁸, —SO₂R⁸, —OCO₂R⁸, —CONR⁸R⁹,—CSNR⁸R⁹, —COR⁸, —OCOR⁸, —N(R⁸)COR⁹, —N(R⁸)CSR⁹, —SO₂N(R⁸)(R⁹),—N(R⁸)SO₂R⁹, —N(R⁸)CON(R⁹)(R¹⁰), [where R¹⁰ is a hydrogen atom or anoptionally substituted alkyl group], —N(R⁸)CSN(R⁹)(R¹⁰) or—N(R⁸)SO₂N(R⁹)(R¹⁰); Alk² is a straight or branched alkylene chain; m iszero or an integer 1; R⁶ is a hydrogen atom or a methyl group; R is acarboxylic acid (—CO₂H) or a derivative thereof; R^(a) is a hydrogen ora methyl group; Ar is an optionally substituted aromatic orheteroaromatic group; and the salts, solvates, hydrates and N-oxidesthereof.
 2. A compound of formula (2):

wherein R, R^(a), R¹, R², R⁶, Alk², m and Ar are as defined above andthe salts, solvates, hydrates and N-oxides thereof.
 3. The compound ofclaim 2 wherein m is one, Alk² is methylene, R⁶ is hydrogen, R^(a) ishydrogen, and Ar is a nitrogen containing heteroaryl.
 4. A compound ofthe formula:

wherein R¹ and R² are independently selected from the group consistingof hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,cycloalkyl, substituted cycloalkyl, or R¹ and R², together with thenitrogen atom to which they are attached, are joined to form anoptionally substituted heterocyclic ring provided that said substitutedalkyl, substituted alkenyl and substituted cycloalkyl do not carry anaryl, substituted aryl, heteroaryl or substituted heteroaryl group; R⁴and R⁵ are independently selected from the group consisting of-L²(Alk³)_(t)L³(R⁷)_(u) in which L² and L³ are independently a covalentbond or a linker atom or group, t is zero or the integer 1, u is aninteger 1, 2, or 3, Alk³ is an aliphatic or heteroaliphatic chain and R⁷is hydrogen or halogen atom or a group selected from alkyl, —OR⁸ [whereR⁸ is a hydrogen atom or an optionally substituted alkyl group], —SR⁸,—NR⁸R⁹ [where R⁸ is a hydrogen atom or an optionally substituted alkylgroup], —NO₂, —CN, —CO₂R⁸, —SO₃H, —SOR⁸, —SO₂R⁸, —OCO₂R⁸, —CONR⁸R⁹,—CSNR⁸R⁹, —COR⁸, —OCOR⁸, —N(R⁸)COR⁹, —N(R⁸)CSR⁹, —SO₂N(R⁸)(R⁹),—N(R⁸)SO₂R⁹, —N(R⁸)CON(R⁹)(R¹⁰), [where R¹⁰ is a hydrogen atom or anoptionally substituted alkyl group], —N(R⁸)CSN(R⁹)(R¹⁰) or—N(R⁸)SO₂N(R⁹)(R¹⁰); Alk² is a straight or branched alkylene chain; m iszero or an integer 1; R⁶ is a hydrogen atom or a methyl group; R is acarboxylic acid (—CO₂H) or a derivative thereof; R^(a) is a hydrogen ora methyl group; and Ar is selected from the group consisting of IIIa,IIIc, IIId, IIIe and IIIf:

wherein R^(5′) is selected from the group consisting of alkyl,substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl,cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, heterocyclic, substituted heterocylic, heteroaryl andsubstituted heteroaryl; R^(6′) is selected from the group consisting ofhydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl,cycloalkenyl, substituted cycloalkenyl, heterocyclic, substitutedheterocyclic, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, and —SO₂R^(10′) where R^(10′) is selected from the groupconsisting of alkyl, substituted alkyl, cycloalkyl, substitutedcycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic,substituted heterocyclic, aryl, substituted aryl, heteroaryl,substituted heteroaryl; R^(7′) and R^(8′) are independently selectedfrom the group consisting of hydrogen, alkyl, substituted alkyl,cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, heterocyclic, substituted heterocyclic andhalogen; R^(16′) and R^(17′) are independently selected from the groupconsisting of hydrogen, alkyl, substituted alkyl, alkoxy, substitutedalkoxy, amino, substituted amino, cycloalkyl, substituted cycloalkyl,aryl, substituted aryl, heteroaryl, substituted heteroaryl,heterocyclic, substituted heterocyclic and halogen; and R^(18′) isselected from the group consisting of alkyl, substituted alkyl, alkoxy,substituted alkoxy, amino, substituted amino, cycloalkyl, substitutedcycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,heterocyclic and substituted heterocyclic; R^(20′) is selected from thegroup consisting of hydrogen, alkyl, substituted alkyl, alkoxy,substituted alkoxy, cycloalkyl, substituted cycloalkyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic,substituted heterocyclic and halogen; R^(21′) is selected from the groupconsisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy,amino, substituted amino, cycloalkyl, substituted cycloalkyl, aryl,substituted aryl, heterocyclic and substituted heterocyclic; b is 1 or2; and enantiomers, diastereomers and pharmaceutically acceptable saltsthereof.
 5. The compound of any of claims 1 to 4 wherein R¹ and R² areboth methyl.
 6. The compound of any of claims 1 to 4 wherein R¹ and R²,together with the nitrogen atom to which they are attached form amorpholino or thiomorpholino ring.
 7. A pharmaceutical compositioncomprising a pharmaceutically acceptable excipient and an effectiveamount of a compound according to any of claims 1-6.
 8. A method forbinding VLA-4 in a biological sample which method comprises contactingthe biological sample with a compound according to any of claims 1-6under conditions wherein said compound binds to VLA-4.
 9. A method fortreating an inflammatory condition in a mammalian patient whichcondition is mediated by VLA-4 which method comprises administering tosaid patient a therapeutically effective amount of a pharmaceuticalcomposition of claim
 7. 10. The method according to claim 9 wherein saidinflammatory condition is selected from the group consisting of asthma,Alzheimer's disease, atherosclerosis, AIDS dementia, diabetes,inflammatory bowel disease, multiple sclerosis, rheumatoid arthritis,tissue transplantation, tumor metastasis, meningitis, encephalitis,stroke, nephritis, retinitis, atopic dermatitis, psoriasis, myocardialischemia and acute leukocyte-mediated lung injury.